Methods and systems for determining vascular bodily lumen information and guiding medical devices

ABSTRACT

Methods and systems for determining information about a vascular bodily lumen are described. An exemplary method includes generating an electrical signal, delivering the electrical signal to a plurality of excitation elements in the vicinity of the vascular bodily lumen, measuring a responsive electrical signal from a plurality of sensing elements in response to the delivered electrical signal, and determining a lumen dimension. Specific embodiments include generating a multiple frequency electrical signal. Another embodiment includes measuring a plurality of responsive signals at a plurality of frequencies. Still other embodiments include using spatial diversity of the excitation elements. Yet other embodiments use method for calibration and de-embedding of such measurements to determine the lumen dimensions. Diagnostic devices incorporating the method are also disclosed, including guide wires, catheters and implants. The methods and systems described herein are advantageous as they do not include injecting a second fluid for the measurements.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application No.13/159,298, filed Jun. 13, 2011, which claims the benefit of U.S.Provisional Patent Application No. 61/383,744, filed Sep. 17, 2010 toGopinathan, and also claims the benefit of foreign priority of IndianProvisional Patent Application No. 1636/CHE/2010, filed Jun. 13, 2010 toGopinathan et al., both entitled “Systems and Methods for Measurementsof Lumen Parameters”, the disclosures of which are incorporated byreference herein.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference to the same extent as if eachindividual publication or patent application was specifically andindividually indicated to be incorporated by reference.

TECHNICAL FIELD

The invention generally relates to methods and systems useful formedical procedures, and more specifically for determining vascularbodily lumen information and guiding medical devices.

BACKGROUND

To investigate the health of vessels or organs in the human body (e.g.,cardiac vessels), it can be important to be able to measure certaininternal characteristics or parameters of those vessels or organs, whichcan provide details related to cardiac diseases and ailments so thatappropriate treatment can be performed. Traditional methods formeasuring dimensions of vessels or organs include intravascularultrasound (“IVUS”) or optical coherence tomography (“OCT”). In bothcases, a source of energy (ultrasound or coherent light) and ascattering sensor (for ultrasound waves or light) are mounted on acatheter and rotated along the axis of the body lumen in order to scanthe inside of the lumen and map out its profile, revealing itscross-sectional area. These methods, however, are either very expensiveand/or are cumbersome. For example, the use of IVUS requires advancingthe ultrasound catheter to a target area, such as a lumen, obtaining theinformation, removing the catheter, combining the information obtainedusing the catheter with an angiogram to provide parameters about thevessel, then proceeding with a medical procedure such as, for examplewithout limitation, a stent delivery procedure. In addition to the costsand time disadvantages, these procedures are also inconvenient to thepatient.

Electrode-based interventional instruments have been explored asalternatives to IVUS and OCT techniques. Some approaches have usedcatheters with two electrodes disposed thereon for determining thecross-sectional area of a blood vessel. In use, the catheter is advancedthrough the blood vessel to a measurement site, and an AC voltage isapplied to the electrodes, producing a current through the blood withinthe vessel. The impedance is measured. A fluid is then injected into thelumen to replace the blood with the fluid, and a second impedancemeasurement is taken. The multiple impedance measurements are then usedto determine the cross-sectional area of the blood vessel between theelectrodes. In order to use these catheters in conjunction with anangioplasty procedure, the catheter is first advanced to the treatmentsite to perform a measurement of the vessel cross-section. Themeasurement device is then withdrawn and a balloon catheter is advancedto the obstructed site in order to perform the dilatation. Since boththe measurement device and the dilatation catheter can be difficult toadvance to the obstructed site, multiple device exchanges have to bemade adding more time and complexity to the procedure.

A dimension-sensitive angioplasty catheter having an inflatable balloonand a plurality of vessel-measuring electrodes has also been described.The electrodes are mounted on the surface of the catheter tube and areindividually connected to the proximal end of the catheter. The catheteralso includes an inelastic balloon. The balloon is adapted to beinflated through the introduction of a suitable fluid into the lumen ofthe tubular member to press the stenotic lesion against the vessel wall.One pair of electrodes is selected for connection to the output of anoscillator, and a second pair of electrodes is selected for sensing asignal that results from conduction through the blood in the vessel. Thetechnique requires injection of fluid into the expander with knownconcentration at the time of making the measurements using theelectrodes, thus adding to the complexity of the procedure. Themeasurement may also need to be timed with the fluid injection creatingroom for inaccuracies and procedural complexity. The repeatability ofmeasurements may be affected if the injected fluid does not clear outthe blood completely in the vessel at the time of the measurements.

A need therefore exists for improved systems and methods for accuratelymeasuring lumen parameters, such as in the cardiac vasculature.

Additionally, typical imaging techniques provide very limitedinformation, especially about blood vessels and the heart. For example,an angiogram, which uses X-Ray imaging modality and a contrast agentinjected into the blood vessel, provides a simple two-dimensionalsnapshot of the blood vessels. These snapshots or images are used toguide a physician during invasive procedures that are needed for avariety of treatments related to coronary conditions. For example, stentdeployment to unblock an artery involves introducing a guide wire and astent delivery catheter along the aorta to the point of the expectedblock, and the stent is subsequently deployed. This procedure reliesheavily on the skill of the physician operating the devices. Typically,the blood vessel can be tortuous and have turns that may not be evidentin a 2-D snapshot. The operators rely on their experience and makeeducated estimations based on the 2-D images to position the stentbefore deploying it. This can lead to inaccurate placements and henceless than ideal treatment. To get more accurate positional informationit may be useful to obtain a three-dimensional rendering of the lumentrajectory.

Some approaches have attempted to generate three-dimensional (“3D”)images of flow structures and their flow lumen using ultrasoundtechnology. For example, some approaches have used multiple 2D slices togenerate a 3D image. These techniques are specific to ultrasound imagingtechniques, and hence require additional equipment to achieve theoutcome.

Some approaches use a method of obtaining at least two complementaryimages to differentiate the structures and the functions in the regionsuch that image segmentation algorithms and user interactive editingtools can be applied to obtain 3D spatial relations of the components inthe region. At least two complementary methods of imaging can be used(e.g., CT and MRI) from which two images are obtained based onidentifying existing known anatomical features. The two images then areused together to form a high resolution 3D image.

Some approaches use a method for reconstructing 3D data records fromendo-lumen 2D section images of a hollow channel, especially a bloodvessel, using an image providing an endo-lumen instrument such as acatheter. 2D images of the hollow channel are prepared and byconsidering a known relative displacement position of the instrument inthe hollow channel for each 2D sectional image a 3D image data record isreconstructed by computer from the image data of the 2D sectionalimages. The described technique requires multiple 2-D images for asingle section of the hollow channel.

Some approaches use an instrument that is moved in a lumen at a definedspeed over a defined distance. The approaches intraluminally record 2Dimages and create a 3D image.

Known techniques require multiple images be made available to obtain a3D lumen assessment and visualization. Further, in some instances, toobtain lumen trajectory in a 3D volume, complete procedural changes maybe necessary, which may not be conducive for adaptation with existingtechniques. Also, the imaging procedures described may be cumbersome andcomplex, and consequently, the medical procedure requires modificationto accommodate the imaging procedure, which sometimes is impractical.There are still needs for methods and devices that can provide 3Dtrajectory of the blood vessel accurately and in a reasonable amount oftime to enable a skilled operator to perform intricate invasiveprocedures with greater confidence.

Imaging vascular lumens is, in general, performed using several types ofendo-lumen instruments, such as Intra Vascular Ultrasound (“IVUS”),Optical Coherance Tomography (“OCT”), Near Infrared spectroscopes (NIR),and other lumen measurement instruments. Typically these endo-lumenmeasuring techniques provide important parametric information that aidsa practitioner in clinical decision making. For example, an IVUScatheter is used to image the lumen and determine the parameters such asCross Sectional Area (“CSA”) of lumen. The practitioner uses thisinformation to make clinical decisions when, for example, determining anappropriate size of a stent to be delivered in the subject.

This parametric information is not, however, co-registered with theimaging modality used, for example, an X-Ray modality. The correspondingpositions where the parameters were measured are not preserved forfurther use. The physician has to estimate and guide the therapyendo-luminal devices to the points of interest (such as areas of minimumcross-sectional area where a stent is to be deployed).

There have been efforts to fuse images obtained from two or more imagingmodalities to locate the position of the endo-lumen instrumentsvis-à-vis the image of the heart or the artery. In this respect, thefocus so far has been to be able to reconstruct a 3D image of the lumenor create a guidance system by using two or more imaging modalities.However, none of these applications address the co-registering ofparametric information with the positional information of the endo-lumeninstruments.

US 2011/0019892 provides a method for visually supporting anelectrophysiological catheter application. An electroanatomical 3Dmapping data of a region of interest in the heart is visualized. A 3Dimage data of the region of interest is captured before the catheterapplication. A 3D surface profile of objects in the region of interestis extracted from the 3D image data by segmentation. Theelectroanatomical 3D mapping data and 3D image data forming at least the3D surface profile is assigned by registration and visualized bysuperimposing on one another. Characteristic parameters are measured forcatheter guidance during the catheter application. The characteristicparameters are compared with at least one predefined threshold value andregulation data for catheter guidance is generated as a function of thecomparison result. The regulation data is integrally displayed andrepresented in the superimposed visualization. The technique describedherein presents complexity in terms of first having a 3D map of a regionof interest, then obtaining 3D image of region of interest, thensegmenting the 3D image to obtain a 3D profile of region of interest andthen superimposing on the 3D map. The characteristic parameters areobtained separately by use of a catheter. A threshold value is used tocompare with the characteristic parameter and then regulation data forcatheter guidance is obtained and displayed. The technique is complexand uses threshold value to provide some regulation data for catheterguidance. The technique, however, fails to co-register the parametricinformation with the positional information for accurate guidance formedical procedures.

US 2009/0124915 describes a method for guidance to an operator toposition electrodes upon a segmented heart model (“SGM”). The SGM isincluded in a map panel on a display screen. A catheter advanced into abeating heart supports one or more electrodes. During a single beat ofthe heart, an image is obtained with darkened portions corresponding tolocations of the electrodes. The image is presented in the same mappanel as the SGM. The current location of the electrodes is confirmedrelative to the SGM, either manually or through automated softwarealgorithms. Electrophysical (EP) data is captured that representselectrophysiological signals of the beating heart at the currentlocation for each of the electrodes. A signal processing algorithm isapplied to the captured EP data in view of the confirmed currentlocation of the electrodes to result in a calculation that is mapped atthe confirmed location of the electrodes. This technique uses a modelingapproach where the catheter is tracked through fluoroscopy guidance andimaged, and the tracked image is used to determine the position ofcatheter electrodes on the previously selected model for the heart. Thecorresponding EP data is then mapped across the locations on the model.The technique provides both computational complexity and again uses apre-selected model for registering the EP data. Mapping on apre-selected model can lead to errors as the heart is in dynamic motionat any given time and the model may not represent the current state forthe images heart

As mentioned herein above, the diagnostic devices (IVUS, OCT, NIR, otherlumen assessment devices) used in the vascular spaces (coronary,peripheral, renal, abdominal aorta, neurovascular, etc.) providediagnostic parameters but do not integrate this information with theposition of the devices with respect to a reference so that otherdiagnostic or therapeutic devices can be guided to the region ofinterest. Therefore there is continued need in the art to assist themedical practitioner in providing relevant information leading to a moreeffective therapy.

SUMMARY

One aspect of the disclosure is a method of determining informationabout a vascular bodily lumen, comprising: generating amultiple-frequency electrical signal at a plurality of frequencies;delivering the multiple frequency electrical signal to a plurality ofexcitation elements in the vicinity of the vascular bodily lumen;measuring an electrical signal from a plurality of sensing elements atleast two of the plurality of frequencies in response to the deliveredsignal; and determining a lumen dimension using the measured electricalsignal at the at least two frequencies.

In some embodiments the measuring step comprises measuring voltagesacross the plurality of sensing elements at the at least two of theplurality of frequencies. The measuring step can include measuringvoltages across the plurality of sensing elements at each of theplurality of frequencies. Determining the lumen dimension can compriseconverting the voltages to one or more lumen dimensions.

In some embodiments determining a lumen dimension comprises determininga lumen cross sectional area using the electrical signal at least two ofthe plurality of frequencies. Determining a lumen cross sectional areacan comprise determining a plurality of cross sectional areas. Themethod can further comprise moving the plurality of excitation elementswithin the vascular bodily lumen while determining the plurality ofcross sectional areas. Determining a cross sectional area can comprisedetermining a cross sectional profile that comprises a plurality ofcross sectional areas at various locations along the length of thevascular bodily lumen. The measuring step can consist of making a singleset of measurements simultaneously. The method can further comprisedetermining a minimum lumen cross sectional area and a reference lumencross sectional area, and can further comprise identifying the region ofblockage.

In some embodiments the method does not include injecting a fluid intothe vascular bodily lumen.

In some embodiments the measuring step comprises measuring theelectrical signals at the at least two frequencies simultaneously.

In some embodiments the excitation elements also perform the function ofthe sensing elements.

In some embodiments determining the lumen dimension comprisesiteratively comparing the measured electrical signal with a modeledelectrical signal to determine the lumen dimension. The comparing stepcan include comparing a measured voltage with a modeled voltage. Themodeled voltage can be based on a modeled lumen dimension. The modeledlumen dimension can be a lumen cross sectional area.

In some embodiments the comparing step comprises comparing the measuredelectrical signal with an electrical signal from a look-up table. Theelectrical signal from the look-up table can be a voltage.

In some embodiments generating a multiple frequency sequence pulsecomprises generating a multiple-frequency sequence pulse having apredetermined peak to root-to-mean-square (rms) ratio. The ratio can beabout 1 and about 2, such as about 1.4, or about 1.

One aspect of the disclosure is a method of determining informationabout a vascular bodily lumen, comprising: generating an electricalsignal; delivering the electrical signal to a plurality of excitationelements in the vicinity of the vascular bodily lumen: measuring aresponsive electrical signal from a plurality of sensing elements inresponse to the delivered electrical signal; and determining a lumendimension, wherein determining the lumen dimension does not includemeasuring a second responsive electrical signal.

In some embodiments measuring the responsive electrical signal comprisesmeasuring a plurality of responsive signals, such as voltages at aplurality of frequencies. Determining the lumen dimension can compriseconverting the voltages to one or more lumen dimensions. Measuring theresponsive signals at the plurality of frequencies can occursimultaneously.

In some embodiments determining a lumen dimension comprises determininga lumen cross sectional area. Determining a lumen cross sectional areacan comprise determining a plurality of cross sectional areas. Themethod can further comprise moving the plurality of excitation elementswithin the vascular bodily lumen while determining the plurality ofcross sectional areas. Determining a cross sectional area can comprisedetermining a cross sectional profile that comprises a plurality ofcross sectional areas at various locations along the length of thevascular bodily lumen.

In some embodiments the measuring step consists of making a single setof measurements simultaneously.

In some embodiments the method further comprises determining a minimumlumen cross sectional area and a reference lumen cross sectional area.The method can further comprise identifying the region of blockage.

In some embodiments measuring the responsive signal does net includereplacing a volume of blood with a fluid.

In some embodiments determining the lumen dimension comprisesiteratively comparing the measured electrical signal with a modeledelectrical signal to determine the lumen dimension. The comparing stepcan comprise comparing a measured voltage with a modeled voltage. Themodeled voltage can be based on a modeled lumen dimension. The modeledlumen dimension can be a lumen cross sectional area. The comparing stepcan comprise comparing the measured electrical signal with an electricalsignal from a look-up table. The electrical signal from the look-uptable can be a voltage.

One aspect of the disclosure is a method of determining informationabout a vascular bodily lumen, comprising: generating an electricalsignal; delivering the electrical signal to a plurality of excitationelements in the vicinity of the vascular bodily lumen; measuring aplurality of responsive electrical signals from a plurality of sensingelements in response to the delivered electrical signal, wherein a firstof the plurality of sensing elements is not equally spaced from secondand third sensing elements; and determining a lumen dimension based onthe measured electrical signals.

In some embodiments the first sensing element is disposed axiallybetween the second and third sensing elements. In some embodiments thedelivering step comprises delivering the electrical signal to the secondand third sensing elements. In some embodiments the delivering stepcomprises delivering a multiple frequency electrical signal to theplurality of excitation elements. The measuring step comprises measuringvoltages across the plurality of sensing elements at the at least two ofthe plurality of frequencies. Determining a lumen dimension can compriseconverting the voltages to one or more lumen dimensions. Determining alumen dimension can comprise determining a lumen cross sectional areausing the measured plurality of electrical signals. Determining a lumencross sectional area can comprise determining a plurality of crosssectional areas. The method can comprise determining a minimum lumencross sectional area and a reference lumen cross sectional area, and mayinclude identifying a region of blockage.

One aspect of the disclosure is a medical device adapted to determineinformation about a vascular bodily lumen, comprising: an elongatedevice; and a plurality of excitation elements and a plurality ofsensing elements disposed on the elongate device, wherein a first of theplurality of sensing elements is not equally spaced from second andthird sensing elements.

In some embodiments the first sensing element is disposed axiallybetween the second and third sensing elements on the elongate device. Insome embodiments the second and third sensing elements are also firstand second excitation elements. In some embodiments the elongate deviceis a guidewire, and wherein the excitation elements and sensing elementsare electrodes. In some embodiments the elongate device is anangioplasty balloon catheter and wherein the excitation elements and thesensing elements are electrodes. In some embodiments wherein theelongate device is a stent delivery catheter, and wherein the excitationelements and the sensing elements are electrodes.

One aspect of the disclosure is a method of providing an elongatemedical device adapted to determine information about a vascular bodilylumen, comprising: selecting an elongate device comprising first andsecond electrical excitation elements thereon, wherein the first andsecond excitation elements are spaced at a distance that is within anestimated range of the vascular bodily lumen diameter; and positioningthe elongate device in the vascular bodily lumen.

In some embodiments the method further comprises exciting the first andsecond electrical elements with an excitation source. The elongatemedical device can have a plurality of sensing elements thereon, themethod further comprising measuring a responsive electrical signal fromthe plurality of sensing elements in response to the excitation.

One aspect of the disclosure is a method for determining a lumentrajectory of a subject in a 3D volume comprising: positioning aplurality of markers in vivo in a lumen, wherein each marker ischaracterized by an original identity; obtaining an image of theplurality of markers; processing the image to determine an observedidentity of at least a subset of the plurality of markers and anobserved spacing between at least two of the plurality of markers;determining a position of at least a subset of markers in a 3D volumebased on the observed identity, the observed spacing, and the originalidentity of the subset of the plurality of markers; and determining thelumen trajectory in a 3D volume based on the position of each marker.

In some embodiments the method further comprises traversing theplurality of markers through the lumen; tracking the observed identity,and the observed spacing at different positions; determining a pluralityof positions of each marker in a 3D space based on the observedidentity, the observed spacing and the original identity of each of theplurality of markers; and determining the lumen trajectory in a 3Dvolume in a 3D volume based on the plurality of positions of eachmarker. The method can further comprise mapping the observed identity atdifferent phases of heart; and determining a phase-dependent lumentrajectory in a 3D volume. The method can further comprise determining acurrent position of each marker in the 3D space by determining a currentobserved identity for each marker, and superimposing the currentobserved identity on the phase dependent lumen trajectory in a 3Dvolume. The method can further comprise placing a reference patch on thesubject, such as using the patch to determine a change in the subject'sposition, or to determine the position of each marker. The method canfurther comprise using the reference patch to determine the viewingangle of the imaging system. The method can further comprise using thereference patch to determine the calibration factor. The plurality ofmarkers can comprise at least two spaced apart electrodes.

One aspect of the disclosure is a lumen trajectory system comprising: aplurality of markers disposed at predefined locations on an endo-lumeninstrument, the instrument configured to be placed in vivo in a vascularbodily lumen; an imaging component adapted to image the endo-lumeninstrument in the lumen; and a processing component adapted to processthe image to determine at least an observed identity for at least asubset of the plurality of markers and an observed spacing between atleast a subset of the markers from the plurality of markers, and todetermine a position of at least a subset of the markers in a 3D spacethat defines the lumen based on the observed identity, the observedspacing, and an original identity of the subset of the plurality ofmarkers, to determine the lumen trajectory in a 3D volume in a 3D volumebased on the position of each marker.

In some embodiments the system further comprises a tracking module totrack a traverse movement of the endo-lumen instrument in the lumen.

In some embodiments the system further comprises a synchronous phaseimaging device to map the observed identity at different phases ofheart, and to determine a phase dependent lumen trajectory in a 3Dvolume in a 3D volume. The processing means can be is configured todetermine a current position of at least a subset of markers in the 3Dspace by determining a current observed identify for at least a subsetof markers, and superimposing the current observed identity on the phasedependent lumen trajectory in a 3D volume.

In some embodiments the system further comprises a reference patchconfigured to be placed on a subject having the lumen. The referencepatch can be used to determine a change in subject position. Thereference patch can be used to determine the position of each marker.The reference patch can comprise a plurality of calibration electrodesarranged in a predetermined pattern, such as a grid. The reference patchcan be placed at a pre-determined orientation with respect to a plane ofimaging of the imaging means. A plurality of markers can comprise atleast two spaced apart electrodes.

One aspect of the disclosure is a lumen translation measurement systemcomprising: a plurality of markers disposed at a plurality of predefinedlocations on an endo-lumen instrument, the instrument configured to bepositioned in-vivo in a vascular bodily lumen; an imaging componentadapted to image the positions of the plurality of markers on theendo-lumen instrument as it translates through the lumen and adapted tocreate a plurality of image frames corresponding to the positions of theplurality of markers on the endo-lumen instrument; and a processingcomponent adapted to process the plurality of image frames to determinethe amount of translation of the endolumen instrument between the imageframes.

One aspect of the disclosure is a method of determining axialtranslation of a medical device within a vascular bodily lumen,comprising: imaging first and second markers on an elongate medicaldevice within a vascular bodily lumen; imaging the axial translation ofthe first and second markers within a vascular bodily lumen in aplurality of image frames; and processing the plurality of images frameto determine the axial translation of the medical device.

One aspect of the disclosure is a method for obtaining a phase dependent3D lumen trajectory: traversing a plurality of markers placed in vivo ina lumen, wherein each marker is characterized by an original identity;obtaining an image of the plurality of markers; processing the image todetermine at least an observed identity for each of the plurality ofmarkers and an observed spacing between at least two markers from theplurality of markers; tracking the observed identity, and the observedspacing at different positions; mapping the observed identity atdifferent phases of heart; and determining a phase dependent lumentrajectory in a 3D volume based on the phases of heart and the observedidentity and observed spacings.

One aspect of the disclosure is a method for obtaining referenceinformation for diagnostic guidance for an in vivo medical procedure,wherein the method comprises: providing lumen trajectory informationcorresponding to a lumen and parametric information corresponding to thelumen; and combining the lumen trajectory information with theparametric information to obtain the reference information fordiagnostic guidance.

In some embodiments the lumen trajectory information is selected fromthe group consisting of a 2D image and a 3D image. In some embodimentsthe parametric information is at least one pressure, blood flow rate,cross sectional area, and combinations thereof. The lumen trajectoryinformation and parametric information can be phase synchronized. Thephase synchronization can be achieved using ECG gating. The trajectoryinformation and parametric information can be synchronized in time. Thesynchronization in time can be achieved using a common clock.

In some embodiments the reference information is represented as at leastone of a reference image or a reference table or a graphicalrepresentation.

In some embodiments the reference information further comprises areas ofdiagnostic interest marked.

In some embodiments the method further comprises displaying thereference information on a graphical user interface.

In some embodiments the lumen trajectory information is obtained from atleast one of an MRI, X ray, ECG, fluoroscopy, microscopy, ultrasoundimaging and combinations thereof.

In some embodiments the parametric information is obtained from at leastone of an microscopy, ultrasound, Intra Vascular Ultrasound (IVUS), NearInfrared spectroscopy (NIR), Optical Coherence Tomography (OCT),vascular optical camera devices, and combinations thereof.

In some embodiments the parametric information includes a MSS sectionalarea obtained using a multiple frequency excitation signal andsimultaneously measuring a responsive signal at each of the plurality offrequencies.

In some embodiments the method further comprises guiding an endo-lumeninstrument in a lumen using the reference information.

One aspect of the disclosure is a method for guiding an endo-lumeninstrument in a lumen to a region of interest, the method comprising:placing the endo-lumen instrument in a lumen; providing lumen trajectoryinformation for the lumen; providing parametric information for thelumen; combining the lumen trajectory information and the parametricinformation to generate reference information for the lumen; imaging theendo-lumen instrument in the lumen to provide a endo-lumen instrumentimage; correlating the endo-lumen instrument image onto the referenceinformation; and guiding the endo-lumen instrument to the region ofinterest.

In some embodiments a fixed reference for a field of view is used. Thefixed reference for the field of view can be obtained by attaching aradio opaque marker patch on a subject. The fixed reference for thefield of view can be obtained by attaching a radio opaque marker patchon an object. The fixed reference for the field of view can be obtainedby an initial marking of at least one anatomic location in the lumentrajectory information. The fixed reference for the field of view can beobtained by using a set of co-ordinates of an imaging system.

In some embodiments the lumen trajectory information is a 2D image or a3D image.

In some embodiments the parametric information can be at least onepressure, blood flow rate, cross sectional area, and combinationsthereof.

In some embodiments the lumen trajectory information and parametricinformation are phase synchronized. The phase synchronization isachieved using ECG gating. The trajectory information and parametricinformation can be synchronized in time. The synchronization in time canbe achieved using a common clock.

In some embodiments the reference information is represented as at leastone of a reference image or a reference table or a graphicalrepresentation.

In some embodiments the parametric information is obtained using theendo-lumen instrument.

In some embodiments the lumen trajectory information is obtained from atleast one of an MRI, X ray, ECG, fluoroscopy, microscopy, ultrasound andcombinations thereof. The parametric information can be obtained from atleast one of microscopy, ultrasound, Intra Vascular Ultrasound (IVUS),Near Infrared spectroscopy (NIR), Optical Coherence Tomography (OCT),vascular optical camera devices, and combinations thereof.

The parametric information can includes a cross sectional area obtainedusing a multiple frequency excitation signal and simultaneouslymeasuring a responsive signal at each of the plurality of frequencies.

One aspect of the disclosure is a diagnostic element comprising: atleast two spaced apart sets of electrodes configured to be placed invivo proximal to a volume of interest in a cardiac vasculature, whereinat least a first set of electrodes from the at least two spaced apartsets of electrodes is configured to receive an input excitation from anexcitation source, and at least a second set of electrodes from the atleast two spaced apart sets of electrodes is configured to receive anresponse voltage signal from the volume of interest and transmit theresponse voltage signal to a measurement device.

In some embodiments the diagnostic element further comprises a supportwire comprising a distal end and a proximal end, wherein the at leasttwo spaced apart sets of electrodes are positioned at a distal end ofthe support wire; and the excitation source and the measurement deviceare positioned at a proximal end of the support wire. The distal end canbe a helically wound coil. The at least two spaced apart sets ofelectrodes can be placed along a length of the support wire atpredetermined positions. The support wire can be a single wire. Thesupport wire can comprise a plurality of wire strands spaced apart by aninsulating material. The plurality of wire strands can be provided in aconfiguration selected from the group consisting of a multi-filarwinding, one or more braided wires, one or more twisted pairs of wires,and one or more winding twisted pairs of wire. The insulating materialcan be a polymer.

In some embodiments the measurement device calculates a voltagedifference between the at least second set of electrodes, based onoutput signals received by the measurement device, wherein the outputsignals are a function of the response voltage signal and wherein thevoltage difference is a function of a lumen dimension of the volume ofinterest. In some embodiments the voltage difference is based on spatialdiversity of the at least two electrodes. The voltage difference can bebased on frequency diversity of the input excitation and the responsesignal. The voltage difference can be based on tissue diversity of thevasculature. The measurement device can be coupled to a display deviceto display the lumen dimension.

In some embodiments at least one of the at least two electrodes is adistributed electrode. In some embodiments at least one of the at leasttwo spaced apart electrodes comprises one or more electrodes. The one ormore electrodes can be arranged in at least one of a straight lineconfiguration, a staggered configuration, or a spatial configuration.

In some embodiments a catheter comprises the diagnostic element, whereinthe catheter is further configured to determine a cross sectional areaof an aortic valve and further determine a prosthetic size for abioprosthetic valve. In some embodiments the diagnostic element is aballoon catheter. The balloon catheter can be further configured todetermine a cross sectional area of an aortic valve and furtherdetermine a prosthetic size for a bioprosthetic valve. The measurementdevice can calculates a voltage difference between the second set ofelectrodes, based on output signals received by the measuring device,wherein the output signals are a function of the response voltage signaland wherein the voltage difference is a function of a balloon dimensionof the balloon catheter.

One aspect of the disclosure is an active guide wire comprising: adistal end comprising at least two spaced apart sets of electrodes,wherein the distal end is configured to be placed in vivo proximal to avolume of interest in a vasculature; and a proximal end configured to becoupled to a measurement device and to an excitation source. In someembodiments the distal end is a helically wound coil.

In some embodiments a first set of electrodes from the at least twospaced apart sets of electrodes is used to send an input signal into thevolume of interest, and a second set of electrodes from the at least twospaced apart sets of electrodes is used to receive an response voltagesignal from the volume of interest. The measurement device can calculatea voltage difference between the second set of electrodes, based onoutput signals received at the proximal end, wherein the output signalsare a function of the response voltage signal, and wherein the voltagedifference is a function of a lumen dimension of the volume of interest.The voltage difference can be based on spatial diversity of the at leasttwo electrodes, frequency diversity of the input excitation and theresponse voltage signal, and/or on tissue diversity of the blood vessel.

In some embodiments the active guide wire is a single wire. The activeguide wire can comprise a plurality of wire strands spaced apart by aninsulating material. The plurality of wire strands can be provided in aconfiguration selected from the group consisting of a multi-filarwinding, one or more braided wires, one or more twisted pairs of wires,and one or more winding twisted pairs of wire.

One aspect of the disclosure is a diagnostic device for measuring lumendimensions comprising: a diagnostic element comprising at least twospaced apart sets of electrodes configured to be placed in vivo proximalto a volume of interest in a vasculature; an excitation source coupledto a first set of electrodes of the at least two spaced apart sets ofelectrodes; a measurement device coupled to a second set of electrodesof the at least two spaced apart sets of electrodes; wherein the firstset of electrodes from the at least two spaced apart set of electrodesis configured to receive an input excitation from an excitation source,and the second set of electrodes front the at least two spaced apart setof electrodes is configured to receive an response voltage signal fromthe volume of interest and transmit the response voltage signal to ameasurement device.

In some embodiments the device further comprises a processor coupled tothe measurement device to calculate a voltage difference between thesecond set of electrodes, based on output signal received at theproximal end, wherein the output signal is a function of the responsevoltage signal, and wherein the voltage difference is used to calculatea lumen dimension of the volume of interest. The processor can be anintegral component of the measurement device. The processor can be splitinto two or more levels, wherein at least one of two or more levelsresides in a host computer. The device can further comprise a displaydevice coupled to the processor to display the lumen dimension. Thedisplay device is configured to display a visual 2D representation ofthe lumen dimension.

One aspect is a method for calibration for use in measurements from aremotely located multi port network, the method comprising: providing anexcitation and measurement entity for exciting the remotely locatedmulti port network and for measuring proximal voltages corresponding toa plurality of distal voltages at the remotely located multi portnetwork; providing a connecting network for connecting the excitationand measurement entity and the remotely located multi port network;providing a plurality of known load networks coupled to the connectingnetwork; measuring a plurality of voltages corresponding to each load ofthe known load networks; and estimating electrical parameters based onthe measured voltages corresponding to the measurement entity and theconnecting network, wherein the electrical parameters are used forcalibration.

In some embodiments the electrical parameters are at least one of Zparameters, Y parameters, S parameters, H parameters, and G parameters.

In some embodiments each load network from the plurality of networkyields at least three voltage measurements. The plurality of loadnetwork can provide at least eight load networks.

In some embodiments the remotely located multi port network is afloating network. In some embodiments the method further comprises usingthe electrical parameters to de-embed the measurements from the remotelylocated multi port network.

One aspect is a method for measuring a plurality of actual voltages froma remotely located multi port network, the method comprising: providingan excitation and measurement entity for exciting the remotely locatedmulti port network and for measuring a proximal voltages correspondingto a plurality of distal voltages at the remotely located multi portnetwork; providing a connecting network for connecting the excitationand measurement entity and the remotely located multi port network;providing a plurality of electrical parameters as calibration parameterscorresponding to the measurement entity and the connecting network;exciting the remotely located multi port network with a knownexcitation: measuring proximal voltages across at least two pair ofports for the remotely located multiport network; and estimating actualvoltages across the at least two pair of ports using the electricalparameters to de-embed the proximal voltages.

In some embodiments the electrical parameters are selected from a groupconsisting of Z parameters, Y parameters, S parameters, H parameters,and G parameters. In some embodiments the remotely located load networkis a floating network. In some embodiments the connecting networkcomprises a plurality of conductor wires. In some embodiments theremotely located load network comprises at least three distal electrodesplaced in vivo in a body lumen. The three distal electrodes can beplaced at the distal end of at least an active guide wire or a catheter.The actual voltages can be used to determine one or more lumendimensions for the body lumen.

One aspect is a method for de-embedding measured distal voltages acrossat least three electrodes placed in vivo in a body lumen, the methodcomprising: providing an excitation and measurement entity for excitingthe at least three electrodes and for measuring proximal voltagescorresponding to a plurality of distal voltages at the at least threeelectrodes; providing two or more conductors as a connecting network forconnecting the excitation and measurement entity and the at least threeelectrodes, wherein the at least three electrodes are at a distal end ofthe two or more conductors; providing a plurality of electricalparameters as calibration parameters corresponding to the excitation andmeasurement entity and the connecting network; exciting the at leastthree electrodes with a known voltage excitation; measuring proximalvoltages across at least two pair of the at least three electrodes; andestimating actual voltages across the at least two pair of the at leastthree electrodes using the electrical parameters to de-embed theproximal voltages.

In some embodiments the electrical parameters are selected from a groupconsisting of Z parameters, Y parameters, S parameters, H parameters,and G parameters. The at least three electrodes can be placed at thedistal end of at least an active guide wire or a catheter. The actualvoltages can be used to determine one or more lumen dimensions for thebody lumen.

One aspect is a system for de-embedding measured proximal voltagesacross at least three electrodes placed in vivo in a body lumen, thesystem comprising: an excitation and measurement entity for exciting theat least three electrodes and for measuring proximal voltagescorresponding to a plurality of distal voltages at the at least threeelectrodes; two or more conductors configured as a connecting networkfor connecting the excitation and measurement entity and the at leastthree electrodes, wherein the at least three electrodes are at a distalend of the two or more conductors; and a processor for estimating aplurality of electrical parameters as calibration parameterscorresponding to the excitation and measurement entity and theconnecting network, and for estimating actual voltages across the atleast two pair of the at least three electrodes using the electricalparameters to de-embed the plurality of proximal voltages. In someembodiments the electrical parameters are selected from a groupconsisting of Z parameters, Y parameters, S parameters, H parameters,and G parameters. In some embodiments the at least three electrodes areplaced at the distal end of at least an active guide wire or a catheter.In some embodiments the actual voltages are used to determine one ormore lumen dimensions for the body lumen.

BRIEF DESCRIPTION OF FIGURES

The features of the disclosure are set forth with particularity in theappended claims. A better understanding of the features and advantagesof the present disclosure will be obtained by reference to the followingdetailed description that sets forth illustrative embodiments, in whichthe principles of the disclosure are utilized, and the accompanyingdrawings of which:

FIG. 1 is a diagrammatic representation of current paths betweenexcitation elements positioned within lumen;

FIG. 2 is a graphical representation showing the magnitude of specificimpedance for various tissue types over a range of frequencies;

FIG. 3 is a graphical representation showing phase of specific impedancefor various tissue types over a range of frequencies;

FIG. 4 is a graphical representation that shows examples of currentvalues that may be provided to a heart tissue over a range offrequencies;

FIG. 5 depicts current filaments when the vessel wall is insulating.

FIG. 6 depicts current filaments when the vessel wall is highlyconducting.

FIG. 7 illustrates a mesh modeling network.

FIG. 7A illustrates an exemplary method of determining a lumendimension.

FIG. 8 illustrates a finite element model of a lumen with a medicaldevice therein.

FIG. 8A illustrates an exemplary method of determining a lumendimension.

FIG. 8B illustrates an exemplary method of determining a lumendimension.

FIG. 9 illustrates an exemplary method of generating and applying amultiple frequency excitation signal.

FIG. 10 is a block diagrammatic representation of an exemplary system.

FIG. 11 shows an exemplary implementation of a pseudo random binarysequence.

FIG. 12A shows the exemplary pseudo random binary sequence in timedomain.

FIG. 12B shows a zoomed portion of the exemplary pseudo random binarysequence in time domain.

FIG. 13 shows the power spectral density of the exemplary pseudo randombinary sequence.

FIG. 14 shows the phase plot of the exemplary pseudo random binarysequence.

FIG. 15 shows an exemplary implementation for orthogonal frequencydivision multiplexed (OFDM) sequence using IFFT.

FIG. 16 shows a time domain signal for the OFDM sequence of FIG. 14 andFIG. 15.

FIG. 17 shows the OFDM Frequency Response for the implementation of FIG.15.

FIG. 18 shows an exemplary implementation for generating a multifrequency composite sinusoid.

FIG. 19 is a diagrammatic representation of an exemplary diagnosticelement and the associated circuitry for measuring a lumen dimension.

FIG. 20 is a diagrammatic representation of an embodiment of anexcitation and measurement device to be used with the diagnostic elementof FIG. 19.

FIG. 21 is a diagrammatic representation of spaced apart electrodes atpre-determined positions according to one aspect of an exemplaryembodiment.

FIG. 22 is a diagrammatic representation of distributed electrodes.

FIG. 23 is a diagrammatic representation of an exemplary embodiment of adiagnostic device.

FIG. 24 shows an overlay image of an output from the measurement deviceand an angiogram image.

FIG. 25 is a diagrammatic representation of an exemplary embodiment ofthe diagnostic device showing exemplary electronics.

FIGS. 26-33 are diagrammatic representations of a few exemplaryembodiments of the active guide wire.

FIG. 34 is a diagrammatic representation of a balloon catheter thatincludes a diagnostic element.

FIG. 35 is a diagrammatic representation that shows an example of rawdata from vasculature in accordance with an exemplary embodiment.

FIG. 36 is a flowchart representation of an exemplary method fordetermining lumen dimensions according to an aspect of the disclosure.

FIGS. 37 and 38 illustrate exemplary methods of determining a lumentrajectory in a 3D volume.

FIG. 38 a illustrates identification of markers on an elongate medicaldevice such as a guidewire.

FIG. 38 b illustrates tracking the markers across a plurality of frames.

FIG. 38 c illustrates changing in relative spacing of electrodes due toviewing angles.

FIG. 39 shows a specific embodiment of the application of the method ofdisclosure to obtain a lumen trajectory in a 3D volume.

FIG. 40 shows a schematic of an exemplary lumen trajectory device of thedisclosure.

FIG. 41 shows an exemplary lumen trajectory device of the disclosure ina simulated use situation.

FIG. 42 shows one exemplary arrangement of one reference patch withmarkers on it.

FIG. 43 shows the exemplary arrangement of one reference patch withmarkers on it in use situation.

FIG. 44 shows another exemplary arrangement of one reference patch withmarkers on it.

FIG. 45 shows a block diagram representation of a lumen trajectorysystem.

FIG. 46 is a flowchart representation comprising exemplary stepsinvolved in a method of the disclosure.

FIG. 47 is a flowchart representation comprising exemplary stepsinvolved in a method of the disclosure.

FIG. 48 is a block diagrammatic representation of an exemplary system ofthe disclosure.

FIG. 49 is a diagrammatic representation of a 2-port network with portvoltages and port currents.

FIG. 50 is a diagrammatic representation of an exemplary embodiment witha multi port network at a distal end and the excitation and measuremententity at a proximal end.

FIG. 51 is a diagrammatic representation of another exemplary embodimentwith a multi port network at a distal end and the excitation andmeasurement entity at a proximal end.

FIG. 52 is a diagrammatic representation of an exemplary embodiment foruse in measuring electrical response from a body lumen.

FIG. 53 is a diagrammatic representation for another exemplaryembodiment with a different configuration for obtaining the measurementsfrom a body lumen.

FIG. 54 is a diagrammatic representation of a multi terminal embodimentused for modeling the system of FIG. 51 and FIG. 52.

FIG. 55 is a diagrammatic representation of a multi port network thatcan use the assumptions of the embodiment of FIG. 53.

FIG. 56 is a diagrammatic representation of a multi port network thatcan uses the method of the invention where 6 degrees of freedom arepresented.

FIG. 57 is a diagrammatic representation of an embodiment with anexemplary 3-port passive network 6 complex impedances.

FIG. 58 is a diagrammatic representation of another embodiment with anexemplary 3-port network.

FIG. 59 is a flowchart for the exemplary method steps of the invention.

DETAILED DESCRIPTION

The devices, systems, and methods described herein combine imaging,precise physical measurement and tissue characterization at a smallerfootprint and at lower cost compared to other standard diagnostictechniques such as, without limitation, Angiography, IVUS, OpticalCoherance Tomography (OCT), Near Infrared Spectroscopy (NIR) and FFR(“fractional-flow reserve”). The techniques described herein can furtheruncover more anatomical details than some other diagnostic approachesand provide several advantages in a variety of uses.

The disclosure herein provides devices, systems, and methods fordetermining vascular bodily lumen or vessel dimensions, such as across-sectional area. Vascular bodily lumen as described herein impliesa bodily lumen of the circulatory system like an artery or vein havingblood as a fluid flowing in the lumen and generally refers to bloodvessels. “Dimension” as used herein includes, without limitation, crosssectional area, diameter, radius, major/minor axis, and any derivativesthereof. Aspects of the disclosure can be applied as stand-alone systemsor methods, or as part of a greater diagnostic or therapeutic device orprocedure. It shall be understood that aspects of the disclosure can beappreciated individually, collectively, or in combination with eachother. Features described in one or more embodiments can be incorporatedinto other embodiments unless the disclosure specifically saysotherwise.

In some embodiments the systems and methods can determine crosssectional area to determine where the cross sectional area is at aminimum in the lumen, and hence identify where a blockage exists. Insome embodiments the disclosure provides for accurate placement anddilation of a stent within the blocked region of the vasculature, withminimal or no need to use additional diagnostic tools to determine andconfirm stent dimensional choices, placement, coverage, and properapposition to the vessel wall. The embodiments herein can addressgeographic misplacement of stems in arteries, other blood vessels, orother lumens, since angiograms can result in inaccurate and subjectivevisual estimates. Geographic misplacement can include longitudinalmisses and/or axial misses. In a longitudinal misplacement, the stent isplaced too far distally or too far proximally, leaving uncovered plaquein some instances. In other instances the stent length may beinsufficient to cover the lesion length, also leaving uncovered plaque.Additionally, post dilation with a balloon can cause injury to thevessel at the edge of a stent if the balloon is inflated too farproximally or too far distally. In an axial miss, the stent to arteryratio may be less than 0.9. That is, the stent is not inflated to atleast 90% of the desired artery diameter. In another form of axial miss,the stent to artery ratio may be greater than 1.3, meaning that thestent is inflated to over 130% of the desired artery diameter.

In some embodiments, determining lumen parameters such as crosssectional area provides accurate, real-time determination of thelocation the blockage in the vasculature and also to indicate thedimensions of the inflated balloon or stent. The systems and methodsherein can, however, be used for any other suitable procedure in anyother suitable portion of the body, such as a TAVI procedure as isdescribed below.

In some embodiments the location of the blockage, or other anatomicalregions of interest, can be identified and the movement of otherdiagnostic devices can be tracked relative to the anatomical region ofinterest. For example, in some embodiments a blockage is identified andregistered with respect to a reference point, such that the movement ofa stent catheter can be tracked relative to the location of theblockage. Other known methods can be used to identify the anatomicalregion of interest.

A first aspect of the disclosure determines vascular bodily lumeninformation. These embodiments involve passing electric current betweenexcitation elements positioned within a vascular bodily lumen or organ(“lumen or organ” is generally referred to herein simply as “lumen”) andmeasure one or more response electrical signals, also referred asresponse signals, using a plurality of sensors, or sensing elements,within the vascular bodily lumen to determine one or more lumenparameters, such as one or more cross-sectional areas of the lumen. Inexemplary methods, the excitation signals are multiple frequencysignals, and the response signals are response voltages simultaneouslymeasured at multiple frequencies (this is generally referred to hereinas “frequency diversity”). The measured response signals across themultiple frequencies are then used to determine one or more lumenparameters, such as one or more cross-sectional areas. In someembodiments the excitation elements, disposed on an elongate medicaldevice, are not equidistantly spaced from one another along the device,and this concept is generally referred to herein as “spatial diversity.”

As used herein, the following terms, without limitation, may be usedinterchangeably to refer to the same or similar devices: “elongatemedical device,” “diagnostic device,” “delivery device,” “guidewire,”“catheter.”

The methods herein exploit distinctive frequency-dependent electricalproperties of various bodily elements such as blood, vessel wall, fattytissue, calcified tissue, etc. to determine lumen parameters. FIG. 2 isa graphical representation of impedance magnitude 106 for various tissuetypes over a range of frequencies 108. Impedance magnitude (absolutevalue of Vin/lin measured in dB) versus frequency (Hz) is provided foraorta 110, blood 112, and fat (average infiltrated) 114. Vin representsvoltage and lin represents current. The plots of impedance magnitude(absolute value of Vin/lin measured in dB) for blood, tissue (aorticvessel) and fat shown indicate that when an excitation (e.g., asinusoidal current (AC), or any other waveform) at different frequenciesis applied in series across the volume of interest (1 cubic millimeter,for example), the impedance magnitude varies depending on the type ofbodily material that occupies that volume.

FIG. 3 is a graphical representation of an example of impedance phase124 (in degrees) for various tissue types over a range of frequencies126. Line 128 represents the impedance phase (angle of Vin/lin measuredin degrees) of tissue (e.g. aortic vessel) across a frequency range of100 Hz to 100 MHz; line 130 represents impedance phase (angle of Vin/linmeasured in degrees) of blood across a frequency range; line 132represents impedance phase (angle of Vin/lin measured in degrees) of fatacross a frequency range. Vin represents voltage and lin representscurrent. The plots of impedance phase (angle of Vin/lin measured indegrees) for blood, tissue and fat shown indicate that when anexcitation (e.g., a sinusoidal current (AC), or any other waveform asdescribed elsewhere) at different frequencies is applied in seriesacross the volume of interest (1 cubic millimeter, for example), theimpedance phase depends on the type of bodily material that occupiesthat volume.

The electrical excitation sequence used to excite the excitationelements is designed so as to simultaneously excite the lumen withmultiple frequencies spanning a suitable frequency range. The frequencyrange is preferably chosen where the various bodily elements (e.g.,blood, fat, plaque, tissue) show distinctively different frequencydependent electrical characteristics, such as in the range shown in FIG.2 and FIG. 3. These differences lead to unique characteristics in themeasured frequency-dependent signals, which help in accurate assessmentof lumen dimension.

FIG. 1 illustrates a representation of an exemplary elongate medicaldevice with electrodes T1-T4 within a vascular bodily lumen. Current isshown passing between excitation electrodes T1 and T2 along currentfilaments 54. Some of the filaments extend solely through the bloodwithin the lumen, and some pass through both blood and through thevessel wall as shown. It is understood that additional tissue, such asfatty tissue or calcified fatty tissue, can be deposited on the lumenwall such that some filaments pass through one or more of blood, lumentissue, fatty tissue, calcified fatty tissue, etc. The total electricalcurrent between terminals T1 and T2 is the sum total of all theindividual current filaments. Terminals T1, T2, T3 and T4, which are inthis embodiment electrodes, are adapted to measure voltages. Thisprovides three unique voltages, V1, V2 and V3 (e.g., the voltage betweenT1 and T3, between T3 and T4, and between T4 and T2). There arealternate ways of measuring the 3 unique voltages. For example, theterminal T2 could be used as a common reference, and the 3 uniquevoltages can be measured between T1 and T2, between T3 and T2, andbetween T4 and T2. This alternate measurement is essentially a linearcombination of the previously stated example of measuring V1, V2 and V3,and they carry the same information. The particular method of measuringvoltage chosen depends on convenience of implementation and the degreeof noise present in each type of measurement.

From FIG. 1, it is evident that the current lines are crowded near theelectrode, and fan out away from the electrode. This effectivelyincreases the impedance that is measured between the excitationelectrodes (also referred to as two-port impedance). The measured twoport impedance would be significantly larger than the impedancedetermined by the formula used for calculating the resistance orimpedance of a cylindrical section of a conducting medium, which isρ*L/A (where ρ is the resistivity of the medium, L is the length of thecylindrical section, and A is the cross-sectional area). In someinstances, a value several times greater than the formula impedance wasobserved. The extra impedance, sometimes called contact impedance orelectrode fringe effects, is a function of the geometry of the electrodeand the conductivity of the medium in which it is in. Even if thecross-sectional area of the lumen is increased to a very large value,the two-port impedance does not fall below a certain value. To alleviatethe effects of contact impedance, a 4-point impedance measurement isused that uses electrodes away from the excitation electrodes and arecloser spaced. With reference to FIG. 1, it can be seen that theelectrical current filaments are fairly parallel to the axis betweenelectrodes T3 and T4. A 4-point measurement would be a measurement takenbetween electrodes T3 and T4 with the excitation occurring between theouter electrodes, T1 and T2. This reduces the effect of electrodegeometry, but not completely unless the excitation electrodes are placedvery far apart. Further, the amount of current passing outside the blood(wall and surrounding tissue) is also influenced by electrode geometry,which cannot be compensated for by the 4 point measurement. Hence theapproach followed in the methods herein includes the effects of thegeometry of the electrodes in the calculations. The methods do notattempt to determine any impedance, but instead use the electricalvoltage distribution at various locations in the region of interest todetermine cross-sectional area. These voltage distributions areinfluenced by both the electrode geometry and the lumen dimensions. Bybuilding equivalent electrical models that include electrode geometry,both of these factors are automatically accounted for in the calculationof the cross-sectional area of the lumen, as is described below.

Spatial diversity of excitation electrodes provides for more accurateand robust estimated lumen parameters. With reference to FIG. 1, somecurrent passes through the lumen while some passes through the lumenwall. If the electrodes are spaced close to one another other, most ofthe current passes through the lumen, while very little of the currentpasses through the wall. In such a situation, the observed voltagesbecome insensitive to wall boundary, and hence the lumen dimension. Onthe other hand, if the electrodes are spaced too far apart, most of thecurrent flows through the wall. In this situation, the voltage becomesinsensitive in small changes in lumen size. In some embodiments, anoptimal spacing exists where approximately half of the current flowsthrough the lumen and the remainder through the wall. This generallyleads to the desired sensitivity to lumen dimensional changes. Theoptimal spacing depends on the lumen dimension and the electricalcharacteristics of the tissues. As a general rule of thumb, for typicalelectrical characteristics of tissue, it has been empirically found thatthe optimal spacing between T1 and T2 is approximately equal to thediameter of the lumen, although the spacings are not so limited. Forfixed electrode spacing, the spacing should be optimized for an entireoperating range of potential lumen sizes. In this case, the spacing isoptimized for a value in the middle of the operating range so thatsensitivity is reasonable throughout the operating range. In analternate method, many sets of electrodes are provided with differentspacings between them. One set is chosen for the procedure depending onthe expected lumen dimension. Alternatively, the first measurement isdone using a default set of electrodes. Based on this measurement, asecond set of electrodes is chosen to obtain a more accurate estimate ofthe lumen dimension.

In the exemplary embodiment in FIG. 1, electrodes T3 and T4 are usedsolely for measurement. More electrodes are, however, possible. The twoshown in FIG. 1 are merely exemplary. The positions of these electrodesare shown roughly uniformly spaced between the excitation electrodes T1and T2. In alternative embodiments the measurement electrodes can bestaggered so that they are not exactly uniformly spaced between T1 andT2. This asymmetry is found to provide additional lumen information. Forexample, when only one measurement electrode (e.g., T3) is used betweenT1 and T2, and is placed exactly in between T1 and T2, the voltagemeasured between T3 and T2 will be exactly half of the voltage betweenT1 and T2. This voltage measurement is independent of the lumendimension, and thus does not provide any extra information. On the otherhand, if the single measurement electrode (e.g., T3) is placed slightlyoff center between T1 and T2, the voltage value between T3 and T2 isdependent on the lumen dimension. In general, if there are manymeasurement electrodes uniformly spaced between the excitationelectrodes, about half of the measurements will not provide anyadditional information, whereas roughly half will provide additionalinformation. Hence, a slightly skewed spacing of electrodes can bechosen to maximize information obtained while using a minimal number ofmeasurement electrodes.

The size of the excitation electrodes corresponding to T1 and T2 have tobe chosen keeping in mind the contact impedance and mechanical andanatomical constraints. Because of mechanical constraints and thewinding nature of the anatomy, the vessel dictates that the sizes arekept as small as possible. If the size is made too small, however, thecontact impedance of the electrode would become the dominant factoraffecting the voltage measurements. Since the contact impedance islargely independent of the lumen dimension, this reduces the sensitivityof the voltage measurements to lumen dimension. Based onexperimentation, the suitable electrode size was found to be one with anouter surface area of about 1 to 2 square millimeters. However this doesnot imply that a size that does not conform to this range is unsuitable.There would be a trade-off with accuracy of lumen dimension estimationand mechanical properties.

FIG. 4 shows a graphical representation for exemplary current valuesthat may be provided to a heart over a range of frequencies. Forexample, maximum permissible current through a heart (in miliamperes)may vary over the range of frequencies. The maximum permissible currentthrough a heart may also vary depending on whether the current isapplied in an abnormal non-continuous manner, abnormal continuousmanner, or normal continuous manner as shown. The embodiments describedherein under operation are designed to use the excitation currentswithin the permissible safety limits. In some embodiments the excitationmay be applied at a specific frequency or at specific sets offrequencies. In some other embodiments the excitation may be appliedover a range of frequencies. In some embodiments, the range could be 40KHz to 10 MHz. In general, the frequency range is chosen so as toprovide maximal differentiation of the electrical properties of theconstituent elements of the electrical network of the region ofinterest.

Because blood, vessel wall, fatty tissue, and calcified tissue each havedistinctive frequency-dependent electrical properties, the totalelectrical current applied, as well as the three measured voltages, havevalues whose magnitudes, phases and frequency dependences depend uponthe relative portion of the current flowing through the blood and thevessel wall. Overall, the frequency-dependent measurements depend uponseveral factors, including the frequency dependent electricalcharacteristics of blood, the diameter of the blood vessel (DBLOOD), thefrequency dependent electrical characteristics of the wall, thethickness of the wall (TWALL), and the electrode geometry and spacing.Referring to the example in FIG. 1, once the values of V1, V2 & V3 overa range of frequencies are determined (or any other number of voltagesmeasured depending on the number of electrodes), it is possible toestimate DBLOOD with a high degree of accuracy through method describedbelow. Optionally, in the process electrical characteristics of bloodcan also be estimated. This may provide additional clinical value interms of physical properties of blood such as hematocrit.

Some prior art approaches to determine lumen size have seriousdeficiencies. For example, one prior art approach attempts to estimatethe lumen diameter using a device which consists of only two terminals.The method uses simplistic electrical representation of the blood andwall and requires injection of a second fluid for the measurements. Asingle frequency is used when passing the excitation current through theterminals, and therefore does not excite through a range of frequencies.The electrical path through blood is represented by a single electricalimpedance. The electrical path through the wall is represented by aparallel impedance. The method involves taking a minimum of twomeasurements—the first measurement is with the existing conditions, andthe second measurement taken after replacing blood with a salinesolution whose electrical conductivity is markedly different from thatof blood. In this approach two assumptions are made: the impedance ofthe parallel electrical path through the wall is unchanged over the twomeasurements; and that the impedance of the “blood” path in the twomeasurements is inversely proportional to the conductivities of themedium. In other words, the impedance Z=K/sigma, where sigma is theconductivity of the blood or saline and K is a constant whose valuedepends on the diameter of the blood vessel and the electrode geometry.The value of Z does not depend upon the electrical characteristics ofthe wall of the vessel.

There are fundamental problems with the above described prior artapproach. First, the parallel path through the wall is not composed of asingle type of tissue. As can be seen in FIG. 1, the electrical pathinvolving the vessel wall has many electrical current filaments thatpass through varying degrees of blood and vessel wall. Additionally, inthe diseased section of the artery there will be varying degree ofplaque of different morphology (calcified, not calcified, fibrous etc.).Thus, the overall impedance of the “parallel path” would depend on theelectrical characteristics of the blood as well in healthy arteries andother plaque tissues in diseased arteries. Hence, during the secondmeasurement, the parallel path would change in impedance since the bloodis replaced by saline. The second problem is subtle but perhaps morecrucial. The assumption of the blood path being independent of the wallcharacteristics is incorrect. As an illustration of this problem, FIG. 5and FIG. 6 depict the electrical current filaments for two extremecases—the first case shown in FIG. 5 occurs when the wall of the vesselis insulating (i.e. the conductivity of the wall is much lower than theblood). The second case shown in FIG. 6 occurs when the wall is highlyconducting. Comparing the two figures, it is seen that for the secondcase in FIG. 6, the electrical current filaments have a distinctlydifferent shape. The filaments are drawn towards the wall where most ofthe current conduction happens. In consequence, the volume of bloodconducting the electrical current is reduced, leading to an effectiveincrease in impedance of the “blood path”.

In this previous approach, the conductance of the wall stays the same,while the conductance of the medium in the lumen is varied. But theeffect is the same when the conductivity of the wall is varied (i.e.,relative conductance is the important factor). While extremeconductivities have been used to illustrate a point, the effect is lesspronounced in most cases but nevertheless present even with moderatechanges of relative conductivities. It is straightforward to verifythese observations objectively using Electromagnetic (EM) simulations.

In addition to the deficiencies of the prior art approach as set forthabove, it also does not vary the frequency of the excitation (i.e.,frequency diversity), nor does it utilize spatial diversity. The lack offrequency diversity generally leads to poor to no discrimination betweenvarious types of tissues. The lack of spatial diversity leads to reducedrobustness. It also reduces sensitivity to the effects of electrodegeometry. The current filaments crowd near the electrodes andprogressively span out away from the electrodes. This effect isinherently captured by measuring the voltages along multiple pointsalong the axis of the wire.

As set forth above, different types of tissue (or non-tissues found inthe body) have different signature in voltage and current relationshipsas the frequency of excitation is varied. For example, as shown in FIG.2 and FIG. 3, a blood vessel, blood, and fatty tissue each havedifferent signatures in voltage and current. In some exemplaryembodiments the methods and systems herein provide an excitation signalsimultaneously at multiple frequencies, and that measure electricalresponses as a result of the excitation signal (i.e., frequencydiversity). These methods and systems allows the measurements to be madesimultaneously, which allows the measurements to be made during the samephase of a heartbeat, such as during the systolic phase of the diastolicphase. This overcomes the difficulty associated with overlaying multiplemeasurements made at different times to account for the phases of theheartbeat. Some exemplary measurements made using the methods describedherein include, for example, but not limited to, lumen dimension, natureof a specific region of the lumen like fat, stenosis, block, artery,blood pressure, blood flow rate, tissue, and the like, and combinationsthereof.

In some embodiments the measured signals are voltages measured between aplurality of sensors, such as electrodes. For example, in reference toFIG. 1, after an electrical signal with a plurality of frequencies isflowed through terminals T1 and T2, voltages V1, V2, and V3 are measuredat each of the frequencies, although any number of voltages could bemeasured based on the number of sensors. Terminals T1, T2, T3 and T4 areadditionally spaced such that the sensitivity of measurement to changesin lumen dimension are maximized, as described above in reference tospatial diversity. The frequency response of V1, V2, and V3 are thenused to estimate a lumen dimension, such as the lumen diameter.

In one embodiment in which one or more lumen cross sectional areas arebeing determined, the electrical path in the area of the lumen ismodeled using a mesh network. One such example is depicted in FIG. 7.There are 2 types of electrical elements, blood elements and lumen wallelements, each representing a unit element of the tissue. Such a meshnetwork is an approximation of the continuous medium that conductselectricity. To reduce the approximation error, a finer mesh can bechosen. The trade-off is between the required accuracy and thecomputational complexity. The more accurate the approximation, the morecomputational complexity is required. In its coarsest form (with theleast accuracy), the mesh is reduced to one element for blood and oneelement for the wall, which is an approach that has been previouslyattempted. Needless to say, this is too gross an approximation.

In the mesh network, the impedance of each blood element is a linearfunction of the lumen cross-sectional area and inversely proportional tothe conductivity of blood. In an alternate formulation, the impedance ofthe blood element can be kept independent of the lumen dimension, butthe number of elements would change based on the lumen dimension. Thelatter is practically inconvenient since the topology of the electricalnetwork is not constant, and the changes allowed in lumen dimension arediscrete steps rather than being arbitrary. Similarly, the lumen wallelements have impedance that depends on the wall thickness as well as onthe electrical conductivity of the wall. Anatomically, the lumen wallmay have multiple layers. For a more accurate model, additional types ofelements may be added to the mesh network. For example, elements relatedto fatty tissue or calcified tissue are included in the model.Additionally, a 3-dimensional mesh may also be constructed for betteraccuracy of modeling.

Given this mesh network and the voltages V1, V2 and V3, which aremeasured over a range of frequencies, the lumen dimension is solvediteratively as follows, and as shown in FIG. 7A. After obtainingelectrical voltage measurements VM1, VM2, and VM3, assume particularfrequency-dependent electrical model parameters for blood, tissue, lumendimension, and wall dimension. Then, using the assumed parameters, solvethe equivalent electrical network and obtain voltages V1, V2, and V3.Then, compare the model voltages with the actual observed voltages. Ifthe differences are not minimal, apply a correction to all of theparameters based on the differences and repeat the solving step. Whenthe differences are minimal, the lumen dimension can be declared basedon the converged geometrical parameters. The steps can be implementedusing standard fitting techniques such as, for example withoutlimitations, least squares fitting methods such as Gauss Newton method,Steepest Descent method, and Levenberg-Marquardt method.

In a second embodiment in which a lumen dimension is being determined,the lumen region, including the blood and lumen wall, is modeled usingan Electromagnetic (EM) simulation tool. The EM tool uses finite elementmethod (“FEM”) to break down the lumen region into smaller elements(e.g. with tetrahedron shapes). One example of breaking down into finiteelements is depicted in FIG. 8. Given the electrical and magneticproperties of the bodily material in the lumen region, the tool appliesfundamental Maxwell's equations of electricity and magnetism to solvefor all voltages and currents in the entire lumen region. An iterativeapproach similar to the method described for the mesh network can beused to determine the lumen dimension. The difference between FIG. 7Aand FIG. 8A is the step of solving the equivalent EM FEM model andobtain voltages V1, V2 and V3 for the given parameters.

In both the iterative methods described above, the lumen dimension isreasonably assumed to be approximately constant in the vicinity of theelectrodes. The typical electrode separation is in the order of fewmillimeters. This means that the lumen dimension is assumed to beapproximately constant over a few millimeters along the axis of thelumen. In most practical cases, the lumen dimension does not changesignificantly within a few millimeters of axial traversal. In the caseof variations within these few millimeters, the estimated lumendimension would be a local average of the lumen dimensions along theaxis. The local average would be representative of the mid-point betweenthe two excitation electrodes. In a typical procedure, the measurementelectrodes would traverse the length of the blood vessel, andmeasurements would be taken at multiple places. Thus the lumen dimensionwould be estimated for different regions of the blood vessel.

In the iterative methods described above and illustrated in FIGS. 7A, 8Aand 8B, it can be noted that, along with the lumen dimension, electricalproperties of the bodily elements are also determined. These include theconductivity of blood and wall. These electrical properties are alsoavailable as output to infer clinical parameters such as hematocrit andcharacteristics of blockages if any (for example calcified blockages).

The EM approach is a much more accurate model for the lumen region thana mesh electrical network, such as is shown in FIG. 7. However, it isalso very computationally complex. The solving step in the EM modelwould generally require a large amount of time. To speed up thecalculations, a modified approach can be taken. In the modifiedapproach, the EM tool is used offline, prior to use within a patient, tocompute voltage distributions for many possible sets of geometricalparameters and frequency-dependent electrical model parameters. Thevalues of the parameters for which the EM simulation is performed coverthe entire operating range of the parameters. EM simulations are donefor discrete (and judiciously chosen) parameter values and a look-uptable is created. For parameter values that are not explicitlysimulated, interpolation is performed. In rare cases the parametervalues may lie outside the range for which EM simulations have beenperformed. In such cases extrapolation is done rather thaninterpolation. Extrapolations generally have larger errors thaninterpolations, but in such cases, it has been found that it did notaffect the accuracy of lumen dimension estimation. Thus, the EMsimulation results corresponding to any possible set of parameters aremade available even before any measurement is actually made. Creation ofthe look-up table is a time consuming task, but one that can be doneoff-line using arbitrarily heavy computing resources. Once the look-uptable is created, the solving step in the EM model becomescomputationally simpler. For the given parameter values—geometricaldimensions for the lumen wall, and frequency-dependent electrical modelparameters—the corresponding voltages V1, V2 and V3 are read out fromthe look-up table. It is possible that interpolation or extrapolation isrequired to obtain the voltage values for the given set of parametervalues. The values V1, V2 and V3 thus obtained would be equivalent towhat would have been obtained if a full EM simulation were to be run forthe given set of parameter values. FIG. 8B illustrates a flowchart forcreating a look up table for voltage responses (the flowchart on theleft side of the figure) and a method of determining lumen dimensionusing the look-up values (the flowchart on the right side of thefigure).

In embodiments in which pulses are delivered in a range of frequenciessimultaneously, measurements can be taken over any frequency range.Measurements may be taken at any frequency range where the resultingplots for the various tissue types vary in shape. For example, as shownin the shaded region 134 in FIG. 3, the shapes of the impedancemagnitude and/or phase curves for aorta, blood, and fat vary over thefrequency range. Measurements may be taken within a frequency range withany degree of frequency step size. Step size may remain the same or mayvary over the frequency range. In some embodiments, measurements aretaken at about 40 KHz to about 10 MHz, where the frequencycharacteristics of impedances of blood, fat and other tissue types showdistinctive differences.

The impedance magnitude and/or the impedance phase, illustrated in FIG.2 and FIG. 3, may be scalable. For example, if measurements are takenfor 1 cubic millimeter of a tissue type, and if the measurements aretaken for 2 cubic millimeters of the same tissue type, the measurementsfor the same tissue type across the frequency spectrum will be somefactor multiplied by the first measurements' value. In another example,if the first set of measurements for a first amount of a tissue typeyields a particular curve over a range of frequencies, the second set ofmeasurements for a second amount of the same tissue type over the samerange of frequencies may yield a curve that is a scaled version of thefirst curve. The difference in one or more dimensions of the tissue mayresult in a factor that is multiplied by the first set of measurements.

The impedance magnitude and/or the impedance phase may also be additive.For example, if measurements are taken for a first amount of a firsttype of tissue, measurements are taken for second amount of a secondtype of tissue, and measurements are taken for a combination of thefirst and second types of tissue, the measurements for the combinationmay include the first set of measurements and the second set ofmeasurements added together. In some embodiments, the first and secondsets of measurements may be weighted by one or more factors. In anotherexample, if the first set of measurements for the first tissue typeyields a particular curve over a range of frequencies, and the second ofset of measurements for the second tissue type yields a second curveover the same range of frequencies, a third set of measurements for acombination of the first and second tissue types may yield a third curveover the same range of frequencies that may be the first curve times afirst factor plus the second curve times a second factor. The factor maybe 1, less than 1, or greater than 1. In some embodiments, scaling onlyoccurs in magnitude and not in phase.

In some embodiments, for a combination of impedance magnitude andimpedance phase measurements taken over a range of frequencies for acombination of tissue types, there may be one set of tissue types ofparticular dimensions that will yield that combination of impedancemagnitude and impedance phase measurements. Thus, the impedancemeasurements taken over the range of frequencies can yield thedimensions of the various tissue types. These dimensions can be used todetermine lumen dimensions, such as blood vessel cross-sectional areas.Thus, the unit electrical properties may be converted into volumetricdata of the environment, utilizing the uniqueness of the combination.

In some embodiments where stimulating is performed over a range offrequencies, a pseudo random binary sequence (“PRBS”) is used and insome embodiments orthogonal frequency division multiplexed (“OFDM”)sequence is used, both of which are described in more detail below.

In some embodiments the excitation signals are delivered through aplurality of electrodes in a target area in the vasculature. FIG. 9shows an exemplary method 10. The method comprises generating a multiplefrequency sequence pulse having a predetermined peak to root-mean-square(rms) ratio (“PAR”) that is close to unity (i.e., 1) at step 12.

The level of excitation (i.e., energy of excitation) is limited due torestriction of peak admissible current into the area of interest.Consider a situation where the maximum current that can be injected intothe body is Imax. The rms value of the current that can be safelyinjected is Imax/PAR, which is lowered if PAR is high. This in turncauses proportionately lower signal-to-noise ratio (“SNR”) of theelectrical responses from the lumen corresponding to the electricalexcitation. A lower SNR causes a poorer accuracy of the final estimates.

In some embodiments the electrical hardware has a limited dynamic range.The receive chain design has to adjust its gain so as to keep the peaksignal instances lower than its dynamic range. For a signal with highPAR, it would lead to lowering of the overall signal energy in thereceive chain. As an example, a PAR of 2 would mean the receive chain isworking at 2× lower signal strength than it could have worked and it cancreate a SNR degradation of up to 6 dB.

Designs with relatively higher PAR values do not necessarily prevent thesystem from functioning. It can potentially make it more inaccurate dueto lowered SNR. Having a lower PAR is preferable. However, systems thatcan operate on a lower SNR or have a very high dynamic range (addedcomplexity and cost in design) can still work with relatively high PARvalues.

In some embodiments, an excitation with multiple frequencies and adesired PAR, i.e. PAR close to unity, is constructed by generating apseudo random sequence. Without being bound to any theory, it is knownthat a pseudo random sequence of length L generated at a sampling of fswould contain discrete un-aliased tones of frequency from 0 (whichcorresponds to a DC frequency) to fs/2, in steps of fs/L. The power ateach frequency (except DC) is equi-distributed while the phase of theindividual tones is uniformly spread over −□ to +□.

One exemplary method of achieving the excitation would be using adigital-to-analog converter (“D/A” or “DAC”) with low noise. D/As havingthe above stated requirements are known in the art, and can beeffectively used with the disclosure herein. The D/A sampling rate needsto be at least double the required maximum frequency of excitation. Thebasic shape of the D/A converter output is a rectangular pulse of widthequal to the time difference between two consecutive samples. It wouldbe understood by those skilled in the art that if the D/A converter thatoutputs a pseudo random sequence is sampled at twice the desired maximumfrequency (fH), it would create a frequency shape that is the product ofthe frequency shape of the basic pseudo random sequence and thefrequency shape of the rectangular pulse (i.e. a Sinc function with thefirst null at fs).

A significant advantage of an excitation based on pseudo random sequencewith a basic rectangular shape is that its PAR is unity. This leads tomaximizing the rms signal power for a given peak amplitude of thesignal. There are further advantages on the performance of electricalhardware. The output of the D/A converter in this implementation hasonly two levels (−A and A), where A is the amplitude of excitation. Thelinearity of the transmit chain is irrelevant since non-linearity onlyproduces a gain error and offset error to the signal. The receive chaindesign is also simplified with a lower PAR since dynamic range andlinearity requirements are less demanding. Another major advantage ofsuch an excitation based on rectangular pulse shapes (of durationts=1/fs) is that the D/A can be excited with a single bit excitation,minimizing the digital noise associated with toggling multiple bitssimultaneously. A minor fall back of the rectangular pulse shape basedapproach is the small drop at higher frequencies of interest due to theroll off of Sinc response (up to about 4 dB at fH=fs/2) which results inproportionate drop in SNR of the information for channel estimation.However this drop in SNR for channel estimation does not impact systemperformance. In alternate implementations, it may be possible to makethe basic pulse shape as close to a Delta function, in which case, thefrequency characteristics would be flat across frequency. However, thisis associated with an increased PAR. The D/A converter output needs tobe filtered effectively to prevent out of band emissions outside theband of interest. The filtering may be accomplished using a passive oran active analog filter with pass band at the region of interest.Filtering results in a small yet insignificant increase in PAR and PARwould still remain substantially close to unity.

In other embodiments, the excitation sequence is constructed as arepetitive orthogonal frequency division multiplexed (OFDM) sequence.The OFDM sequence consists of equal amplitude of all frequenciesstarting from a low frequency of interest to a high frequency ofinterest. The number of frequencies excited is proportional to the ratioof the high frequency (H) to the low frequency (fL), while the spacingbetween frequencies is the same as the lowest frequency (fL) of interestthat is chosen. The duration of the basic OFDM sequence is inverselyrelated to its lowest frequency. The PAR of the OFDM sequence can bemade to a low value close to unity by a suitable choice of phase foreach frequency. In some embodiments, the PAR of the OFDM sequence iskept lower than 1.4. An OFDM based sequence is a sum of several discretetones whose number is a power of 2, and provides distinct advantage ofimplementing the processing circuitry in an efficient manner based onFast Fourier Transform (FFT).

In yet other embodiments, the excitation sequence can be constructed asadditions of multiple coherent sinusoids with a method that wouldminimize the overall PAR of the sequence. PAR minimization can beachieved by suitably adjusting the phase of each sinusoid. Suchsequences can also be constructed by appropriately dropping out one ormore tones from the OFDM sequence. These sequences are particularlyuseful over a full-fledged OFDM sequence where the electrical hardwaremay not handle a large set of frequency information due to its limitedcapacity or, the non-linearity is too high and dictates the use of tonesthat have non-multiplicative relationship with each other, so that thenon-linear effect of one or, more tones do not impact another tone.

It will be appreciated that the admissible rms current into the body isa function of frequency for a single frequency excitation. Theadmissible current levels are at a minimum of 10 uA and increaselinearly with the frequency beyond 1 KHz. Approaches to this point havenot described admissible current levels for multi-frequency excitations.FIG. 4 shows a graphical representation 16 of exemplary current values18 that may be provided to a heart over a range of frequencies 20. Forexample, maximum permissible current through a heart (in milliA) mayvary over the range of frequencies. The maximum permissible currentthrough a heart may also vary depending on whether the current isapplied in an abnormal non-continuous manner, abnormal continuousmanner, or normal continuous manner. One possible way of determining thevalue of rms current for an excitation based on multi-frequencyexcitation sequence can be by matching the rms current of the compositesignal to the corresponding admissible rms current for the lowestfrequency.

The exemplary method 10 in FIG. 9 also includes delivering the multiplefrequency sequence pulse across the set of electrodes placed in vivo 14.The excited set of electrodes then sends a pulse of electric currentacross the region of interest. Depending on the nature of the region ofinterest, a voltage is developed across the lumen in which theelectrodes are positioned. There will be one voltage corresponding toeach excitation frequency from the multiple frequency pulse. A vastamount of information can therefore be simultaneously obtained using themethods described herein.

Upon the excitation, the plurality of voltages developed across thelumen may then be detected using an appropriate measurement device thatis capable of handling the signals simultaneously. Different types ofbodily material have different signature in voltage and currentrelationships as the frequency of excitation is varied, as describedabove. For example without limitation, a blood vessel, blood, and fattytissue have different signatures in voltage and current. The measurementdevice(s) may be configured to process the multiple sets of informationsequentially, in parallel, or in groups to provide results.

The systems and methods herein provide the capability of making multiplemeasurements of a lumen at the same time. Because they are made at thesame time, all the measurements are made during the same phase ofheartbeat, such as in the systolic phase or diastolic phase. Thisovercomes the difficulty associated with overlaying multiplemeasurements made at different times to account for the phases of theheart.

The methods of use described herein can be administered effectively inthe form of a software program, or algorithm. Thus, in another aspect,this disclosure provides algorithm(s) that performs the methods herein.In some embodiments the software includes algorithm steps adapted togenerate multiple frequency pulses as described herein. The software mayalso be configured to then excite the set of electrodes with themultiple frequency pulse. The software may be configured to subsequentlyreceive the multiple signals from the lumen to be processed. Further,other components that may be used with the algorithm include, forexample without limitation, a display module such as a monitor having asuitable resolution, an input module such as a keyboard, a mouse, etc.

In yet another aspect, the disclosure provides systems, includingalgorithms, that are adapted to perform the methods described herein.FIG. 10 shows an exemplary system 30 comprising at least a set ofelectrodes 32 configured to be placed in vivo in a lumen. The set ofelectrodes is capable of being excited by a multiple excitation pulse.The multiple excitation pulse is made possible using pseudo randomgenerator that involves using a suitable number of flipflops 34. Thenumber of flipflops desired depends on the complexity of the pulse to begenerated, among other factors. The exact sequence to be executed by thepseudo random generator may be inputted using an input module 36. Theinput module may be configured to take manual inputs, or may beconfigured to automatically generate a sequence for the pseudo randomgenerator to execute. As mentioned herein above, instead of a pseudorandom sequence a OFDM sequence may also be used with the associatedelectronics for generation of the OFDM sequence as would be known to oneskilled in the art.

In system 30, the multiple excitation pulse generated is then sentthrough a D/A converter 38. The system further comprises a filter 40,which may be a passive or an active filter, depending on variousfactors, such as, the necessity, the requirement of the situation,computing abilities, cost, and etc., and combinations thereof. In onespecific embodiment, the filter comprises a passive multi-stage LCladder network. Depending on the application, some embodiments can workwithout the need of such a filter.

The system further comprises a processing device 42 adapted to processthe input for a pseudo random generator. The processing device may alsobe configured to send the multiple excitation pulse to the set ofelectrodes. The system may also comprise a communicating device (notshown in FIG. 3) to communicate the pseudo random generator with the setof electrodes. The communication between different components andmodules may be achieved through any wired or wireless means known tothose skilled in the art, and the exact requirement may be arrived atwithout undue experimentation.

System 30 also comprises a detector module 44 to detect the voltagesdeveloped across the lumen, which are described above. The detectedsignals may then be fed into processing device 42 for furtherprocessing. The signals may give rise to a wealth of information relatedto the lumen, which the processing device is configured to determinebased on inputs such as, but not limited to, the signal, the algorithm,the lumen characteristics, and the like. Thus, the system of theinvention may be used to make multiple simultaneous measurements of thelumen, without having to resort to stitching of data acquired atdifferent time points which may introduce errors into the finalmeasurement.

Example 1

In an exemplary implementation, the excitation frequency band was chosenbetween 40 KHz (fL) to 10 MHz (fH) based on the electricalcharacteristics of blood, tissue and fats. A 16 bit D/A converter waschosen to operate at a sampling rate of fs (=20 MHz). The chosen D/Aconverter accepts offset binary sequence (0x0000 for the lowest valueand 0xFFFF for the highest value). The Most Significant Byte of theconverter is toggled according to the single bit pseudo random pattern,while the next bit was kept permanently at logic 1. All other bits werekept at logic 0. Hence the D/A input toggles between 0x4000 and 0xC000,depending on a 0 or a 1 from the pseudo random generator. The pseudorandom generator resides on a back end entity and is comprised of achain of 9 D-flipflops referred to as flops, to represent a 9-tap pseudorandom sequence. The resultant sequence is a maximal length pseudorandom sequence with length of L=511 (29−1). The generator polynomialused to generate the sequence is

X9+X4+1=0  (1),

which would mean that the input of the last tap is an xor-ed output ofthe first and the fifth flops, as shown in FIG. 11. The flop outputs areall initialized to 1's to begin with (Reset condition). The tonespresent in the excitation sequence are multiples of fl, wherein:

fl=fs/L=20/511 MHz=39.14 KHz  (2)

The D/A converter produced an output with frequencies spaced at 39.14KHz. The output was passed through a bandpass filter whose pass bandstarts at a value lower than 39.14 KHz and ends above 10 MHz ensuringdecent flatness over the entire band. In the specific implementation,the filter is designed using a passive multi-stage LC ladder network.Since the minimum frequency of the final composite signal is at 39.14KHz, the signal rms value is maintained to be lower than 391 □A. Thechoice of the sampling frequency and the tap length depends on theminimum and maximum frequencies of operation. As described before, thesampling frequency is at least twice the maximum desired frequency inthe excitation, while the tap-length (L) is the nearest integersatisfying the relationship

L=[log 2(fs/fmin)]  (3)

FIG. 12 a shows the time domain waveform of the 9-tap pseudo randombinary sequence generated as described herein. The waveform has anamplitude of 391 □a. FIG. 12 b shows a highlighted portion of theexemplary pseudo random binary sequence in time domain.

FIG. 13 shows the power spectral density of the same 9-tap pseudo randombinary sequence generated. FIG. 14 shows the plot between phase angleand frequency for the 9-tap pseudo random binary sequence.

Example 2

In yet another implementation, as shown in FIG. 15, an OFDM sequence isconstructed using Nfreq (=256) discrete tones of equal amplitudes andeach being at a random phase. The phase angles for each tone areadjusted so as to obtain the PAR lower than 1.4. The construction of theOFDM sequence can be done either simply by adding all the discrete tonestogether or, by performing a IFFT (Inverse Fast Fourier Transform) of asymmetric sequence of 2Nfreq (=512) complex numbers, where the first 256complex numbers relate to the amplitude and phase of the individualtones and the next set of 256 complex numbers are simply the complexconjugate of the first 256 arranged in the reverse order (FIG. 15). Theresultant time domain signal is shown in FIG. 16 that is sampled at fs(=20 MHz) which is twice the largest frequency of interest (fH). Thelowest frequency in this sequence is fL (=fs/2Nfreq 39.0625 KHz). Thetime domain OFDM sequence can also be produced at higher sampling ratesusing appropriate size of IFFT inputs keeping the lowest frequency same.A higher sampling rate cases the requirement on anti-aliased filteringwhile increasing the complexity of the hardware in the transmit side.FIG. 17 shows an exemplary OFDM frequency response for theimplementation of FIG. 15.

In yet another embodiment as shown in FIG. 18, a customized sequence iscreated using multiple coherent sinusoids added with appropriate phaseangles so as to minimize the PAR. The resultant sequence may bear theproperty where any given frequency is not harmonically related to anyother frequency. The same can also be constructed in the OFDM frameworkdescribed above, where one or, more IFFT inputs are nulled to remove aset of tones from the original sequence.

As referenced above, some embodiments also utilize spatial diversity,which generally refers to a difference in separation between electrodes.For example, voltage measurements may be taken between a first electrodeand a second electrode that are at a distance from one another, andmeasurements may be taken between a first electrode and a secondelectrode that are at a second distance from one another. With spatialdiversity the first and second distances are different. In otherembodiments any number of electrodes may be used, and the distancesbetween any two electrodes can be different from the distance betweenany two other electrodes, as is described above. Using different spacingbetween electrodes provides different voltage measurements for the samelumen dimension. Using all these sets of measurements to solve for acommon lumen dimension leads to increased robustness. There are tworeasons for this. First, the optimal electrode spacing depends on thedimension of the lumen being measured. Since the dimension is not thesame in different cases, using such spatial diversity allows at leastone set of electrodes being optimally or nearly optimally spaced.Secondly, some of the measurements can be affected by other factors thatreduced its reliability. Some of the factors are (1) the touching of thespecific electrode with the wall leading to anomalous measurement (2)Glitches in the measurement circuitry leading to incorrect voltagemeasurements for some electrodes. In these cases, some of themeasurements can be identified as outliers and discarded, leading to amore accurate lumen dimension estimation.

In some embodiments above the methods are described as providingexcitation pulses across at least two electrodes. Exemplary deliverydevices that can be incorporated into an overall system will now bedescribed. The delivery devices can, however, be considered stand-alonedevices. FIG. 19 is a diagrammatic representation of an exemplaryembodiment of a diagnostic element. Diagnostic device 15 includes anelongate medical device on which at least two spaced-apart sets ofelectrodes 16 and 17 are disposed near distal end 18. Diagnostic device15 is configured to be placed in vivo proximal to a volume of interest19 in a vasculature, for example a blood vessel, wherein a first set ofelectrodes is configured to receive an input excitation from excitationand measuring device 20, and a second set (or the first set) ofelectrodes is configured to receive a voltage signal referred to hereinas an “response,” or “responsive” voltage signal from the volume ofinterest 19. The second set of electrodes is configured to transmit theresponse voltage signal to excitation and measurement device 20 atproximal end 22 of the elongate medical device. Excitation andmeasurement device 20 receives and measures an output signal that is afunction of the response voltage signal, and the output signal isprocessed to calculate a voltage difference between the spaced apartelectrodes. The voltage difference is indicative of a lumen dimension,and is used to calculate one or more lumen dimensions. A set ofelectrodes has been referred to for measuring the signals from thevolume of interest, however the device may have any number ofelectrodes. An exemplary advantage of the exemplary embodiment in FIG.1, and the other embodiments herein, is that the system does not requirethat fluids be injected into the body lumen for obtaining themeasurements. Additionally, the exemplary embodiment provides a directmethod for obtaining the lumen parameters, increasing the ease of theprocedure and the patient comfort.

FIG. 20 shows an exemplary non-limiting embodiment of excitation andmeasurement device 20 of FIG. 19. Excitation source 24 is used forexciting a set of electrodes of diagnostic element 15 via referenceresistance 26, and the voltage measurements VM1 28, VM2 29, VM3 23, andVM4 25 (also referred to as output voltages in the description ofspecific embodiments) are received and measured after the excitation. Itwould be appreciated by those skilled in the art that other topologiesfor making these measurements are possible and are included herein.Measurements, such as electrical measurements as shown, may be takenbetween two or more electrodes. The voltage distribution, for a givenexcitation with frequency diversity, between the two electrodes may bemeasured continuously as the diagnostic element is advanced through thevessel. As mentioned earlier, the voltage distribution between theelectrodes is indicative of the cross-sectional area of the lumen orvolume of interest with the lumen, and is used for determining theselumen dimensions.

The spaced apart electrodes of the diagnostic element may be arranged onthe elongate element at pre-determined positions indicated by referencenumerals 35 through 48 as shown in FIG. 21. The size and spacing ofelectrodes are designed for optimal performance. The electrodes may bemounted on a catheter or on a guide wire for placing them in vivo in thebody lumen. In some embodiments, electrodes may be formed of aconductive material. For example, electrodes may include a metal, suchas copper, silver, aluminum, gold, or any alloys, plating, orcombinations thereof. Electrodes may include exposed portions of wires.Electrodes may include any electrically conductive material inelectrical communication with electronics for providing and/or receivingan electrical signal and/or current.

The electrodes may also be arranged as distributed electrodes 50 asshown in FIG. 22 where multiple electrodes may be used. The distributedelectrodes refer generally to a distributed electrode configurationwhere a single electrode is split into many and placed in severallocations and are all connected to the same terminal. There are severalways for achieving the distributed electrode configuration and FIG. 22is one non-limiting example. Here, several electrodes are connected tothe same excitation source by shorting them through internal wires andthus achieving a distributed electrode configuration.

Additional different configurations of electrodes are possible fordifferent aspects and some non-limiting examples are described herein.In one specific example the diagnostic element comprises three spacedapart electrodes, and in another example the diagnostic elementcomprises four spaced apart electrodes. In alternate embodiments, anynumber of electrodes may be used.

Further, the spacing between electrodes may be asymmetric with respectto a guide wire on which the electrodes are mounted. In yet anotherexample, the electrodes do not surround the wire completely. Only asector of the wire is covered by an electrode. Multiple such electrodesare placed covering different sectors of the wire. Specific electrodesare chosen such that they are most favorable. For instance, if the wireis touching the wall or the stent, it would be more favorable to use anelectrode that covers a sector of the wire that is away from the wall orstent. It may be noted that in some configurations, the electrodesadapted to send the input excitation and the electrodes adapted totransmit the response signals may be pre-determined. Further it ispossible to select more than one pair of electrodes to send the inputexcitation and similarly more than one pair may be selected to transmitthe response voltage signal.

In yet another example the distance between each of the electrodes inthe pair of electrodes may not be pre-determined, but the location ofeach electrode is deterministic by any known techniques. In some otherembodiments, the distances between each of the electrodes may be fixed.In other embodiments, distances between electrodes may vary. In specificmethod of use, electrodes may be positioned in close proximity to ananatomical feature. For example, electrodes may be positioned in closeproximity to a body lumen, such as a blood vessel, where the electrodesmay contact the outside surface and/or inside surface of the body lumen.In some embodiments, the electrodes may be positioned within a bodylumen while touching or not touching the body lumen. Each of theelectrodes may be similarly positioned with respect to the body lumen(e.g., all electrodes contacting the outside surface of the body lumen),or various electrodes may have different positions with respect to thebody lumen (e.g., some electrodes within a body lumen, some electrodescontacting the inner surface of the body lumen).

Further, in some embodiments, a guide wire may be integrated with thediagnostic element. The guide wire may also comprise multiple terminalsthat are spaced apart. In a specific example a first terminal and asecond terminal are used that are spaced apart by a separator therebetween. The separator may comprise a polymer. The separator may be, insome embodiments, a non-conductive coating around the first terminal andthe second terminal. The separator may electrically isolate and/orinsulate the first terminal from the second terminal. The separator maycomprise, but is not limited to, polypropylene (PP), polyimide, Pebax,polyphenylene oxide (PPO), polystyrene (PS), high impact polystyrene(HIPS), acrylonitrile butadiene styrene (ABS), polyethyleneterephthalate (PET), polyester (PES), polyamides (PA), polyvinylchloride (PVC), polyurethanes (PU), polycarbonate (PC), polyvinylidenechloride (PVDC), polyethylene (PE), polycarbonate/AcrylonitrileButadiene Styrene (PC/ABS), any other polymer, rubber, a thin walledheat shrink material or any other electrically insulating material. Theelectrical conducting wires may be made of copper, drawn tilled tube(e.g., Fort Wayne metals or alike) stainless steel, silver alloy,tungsten or any other non-toxic electrically conductive material, chosenon the basis of their electrical and mechanical properties forparticular applications. The electrical wires may further be insulatedusing extrusion, enamel coating, spray, or dip coating processes andusing biocompatible insulating materials whose mechanical properties areappropriate for the application.

In some embodiments, the guide wire may also comprise a third terminaland a fourth terminal and wire. Separation and/or separators may beprovided between the first, second, third, and/or fourth terminal. Anynumber of wires connected to discrete terminals may be provided invarious embodiments of the invention. As would be appreciated by thoseskilled in the art, electrical insulation may be provided between theplurality of wires.

Separate electrically conductive wires or conductor wires may beadditionally used or may be integrated with the guide wires and are usedto connect the distal electrodes to the proximal end. These conductorwires may also be embedded either inside or the outside of a guide wire.In some case, the guide wire support itself can be employed as one ofthe aforementioned conductor wires. In a specific non-limitingembodiment, the guide wire may have a hypotube construction that wouldbe well understood to those skilled in the art. In one particularnon-limiting example, a conductor wire or multiple conductor wires maybe wrapped on an outside surface of the core wire and encased within anexternal hypotube or within a polymeric material (e.g. heat shrink, orextruded polymer).

In another embodiment, a surface of the guide wire may have patternssuch as and not limited to laser cut patterns to provide variablestiffness along the length of the guide wire. It would be appreciated bythose skilled in the art that at different lengths different stiffnesslevels may be needed for ease of movement of the guide wire being placedin vivo inside a patient's body and these stiffness requirements may bemet by providing different patterns on the surface of the guide wire.The stiffness may also be varied by providing different thicknesspolymer jackets around the guide wire. The guide wire may be a round ora flat wire depending on the desired application.

The attachment of electrodes with the wires may be achieved by usingdifferent techniques including but not limited to providing a slit inthe electrode to route the conductor wire, crimping the electrode on theconductor wire and then laser welding, soldering or brazing theelectrodes on the wires. In another example a hole may be provided inthe electrode to attach the conductor wire. Electrodes may also beprovided as coils that can be held on the hypotube by means such weldingor bonding. Electrodes may also be provided as rings or bands mounted onthe conductor wires. In another embodiment that uses guide wires,multiple electrodes in the coiled section of the guide wire can beimplemented by exposing the coil to the blood by avoiding thenon-conductive coating at the required places. To create multipleelectrodes, a multifilar winding can be used and different mutuallyinsulated wires can be exposed at the requisite places.

Further, in some embodiment the electrode terminals may be provided onseparate wires which may or may not share a common support or activeguide wire. Terminals may be arranged in a straight line. In otherembodiments, terminals may be provided in a staggered configuration,within a planar arrangement, within a spatial arrangement, or may haveany other location relative to one another. For all combinations ofterminals, measurements may be provided responding to the same currentand voltage values.

In some embodiments the electrodes are called leads, and are configuredmuch like other coronary leads known in the art, but are configured tobe part of the active guide wire. Some embodiments comprise more thantwo electrodes. In some embodiments one or more electrodes arepositioned on a portion of the active guide wire's circumference at itsdistal end on the active guide wire. In some embodiments one or moreelectrodes encompasses the active guide wire's entire circumference atits distal end on the active guide wire.

In other embodiments sectorially-spaced electrodes may be provided.Sectorially spaced electrodes do not go completely around the activeguide wire. This will allow an azimuthal delineation of the blockagei.e. the spatial orientation or plaque in a given cross section maybefeasible to determine as opposed to only cross section area. Since theyonly go around a portion of the active guide wire, the direction of thedimensions measured will be on the side of the active guide wire thatthe sectorially spaced electrode is on. In some embodiments, sectoriallyspaced electrodes may all be positioned on the same side of the activeguide wire. Alternatively, they may be provided in varying axiallocations around the active guide wire. As previously mentioned, otherembodiments of the invention may provide other winding or braidingtechniques for the wires.

An active guide wire may include a support with one or more wire wrappedaround. The wires may have any configuration, which may include thetypes of windings or braiding previously described. The core of theactive guide wire may have any diameter. In some embodiments, thediameter of the core may remain the same for the length of the core. Inother embodiments, the diameter of the core may vary along the length ofthe core. There may be sections where the diameter of the core mayremain the same for sections of the core, and may vary for othersections of the core. In some embodiments, the diameter of the core maybe greater toward a proximal end of the active guide wire, and may besmaller toward a distal end of the active guide wire. In someembodiments, a standard diameter may be provided in a normal section,and a larger diameter may be provided in an x-support section.Similarly, the cross-sectional shape and size of core may remain thesame or vary along the length of the active guide wire.

In some embodiments, one or more wires may be wrapped around the core ofthe active guide wire. In some embodiments, the wires may have sectionswhere the coating is ablated and metal is exposed, as previouslydescribed. Such ablated sections may occur anywhere along the length ofthe active guide wire. In some embodiments, the active guide wire mayhave a flexibility zone and a stent zone. In some instances, the ablatedsections may be provided within the stent zone. In other embodiments,the ablated sections may be provided in the flexibility zone, oranywhere else along the active guide wire.

In some embodiments, the wires may be wrapped so that they have varyingdegrees of floppiness. For example, a standard configuration may havethe wires be rigid, or not floppy. In an intermediate configuration, thewires may be slightly floppy. In other configurations the wires may bewound to be floppy or extra floppy. The type or tightness of wirewinding or braiding, or the materials of wires or coatings, may beselected to provide a desired degree of floppiness.

In some embodiments, a proximal end of the active guide wire may beformed of a plastic, such as PTFE, or any other type of polymerdescribed elsewhere herein.

In some other embodiments, a section of the active guide wire mayinclude a spring coil. In some implementations, the spring coil may beformed of a material that is different from the rest of the wire. In oneexample, the spring coil may be formed of a platinum alloy. Furthermore,in some embodiments, the active guide wire may include a hydrophilicand/or hydrophobic coating.

FIGS. 26-34 illustrate exemplary embodiments of active guide wires. FIG.26 shows active guide wire 200 with core shaft 202 upon which insulatedelectrode wire 204 (also referred herein as conductors or conductorwire) run in parallel. Jacket 206 is disposed over the core wire andconductor assembly and reflowed for desired diameters. In anotherembodiment shown in FIG. 27, guide wire 208 includes conductor wires 204that are drawn from the hollow 210 of core 202 and core 202 is coveredby jacket or heat shrink 206 that can be sleeved, shrunk or extrudedover the surface of the core shaft. In another embodiment of guidewire212 as shown in FIG. 28, conductor wires 204 are wrapped around coreshaft 202. The outer jacket 206 may be extruded, sleeved and reflowedover the conductor wires. The distal end of the conductor wires may bemade of more flexible materials to be drawing into electrode terminalsand make a floppy transition at the tip.

Another embodiment of guidewire 214 shown in FIG. 29 has conductor wires204 braided over central core shaft 202. The proximal end of theconductor wires may be stiffer and the distal end may be flexible. Inaddition, the entire active guide wire may be made stiffer at theproximal end and flexible at the distal end. The jacket 206 may beprovided to cover the braided conductor wires by any of the techniquesas described in reference to other embodiments. In yet anotherembodiment of guidewire 216 as shown in FIG. 30, an extrusion wire mayhouse the conductor wires 204 running internally making a main shaft andthe proximal and distal ends may have a different configuration on whichthe electrodes may be mounted. In yet another embodiment of guidewire218 as shown in FIG. 31, an inner extrusion shaft 220 may have asuitable groove 222 to accommodate the conductor wires 204. An outersleeve 206 may be heat shrunk over the inner shaft. In yet anotherembodiment as shown in FIG. 32, the outer shaft 226 may be braided forstiffness and polymer may be reflowed over the top of the outer shaft toform a jacket 206. The conductor wires 204 may be drawn out from acentral core 228. In yet another embodiment 230, a coil 232 may besleeved over the outer shaft 234 as shown in FIG. 33, while theconductor wires 204 are drawn from a core 236 of the outer shaft.

In some embodiments, the device, which may or may not include an activeguide wire, may be provided in a balloon catheter. Embodimentsincorporating a balloon catheter may have some or all of the aspectsdescribed elsewhere herein, and may perform the same measurements. Insome embodiments, electrodes may be provided in front of the balloon,behind the balloon, and/or on top of the balloon.

FIG. 34 illustrates exemplary balloon catheter 238 that includes thediagnostic elements described herein. Distal end 240 of the catheter hasfour spaced apart electrodes 242 disposed thereon, and another set ofelectrodes 244 inside the balloon. The catheter also has markers 246inside the balloon. Though only two electrodes are shown inside theballoon, there may be multiple electrodes. In this exemplary,non-limiting configuration, the distal end electrodes aid in measuringthe lumen dimensions and the electrodes inside the balloon aid indetermining the balloon diameter during the inflation process. Thedistances x, y, z and a, b, c, d as shown in the drawing, may bepredetermined during the design of the balloon catheter. In anotherembodiment, electrodes may be present only inside the balloon. Inanother embodiment, electrodes may be present only outside the balloon.

A balloon catheter may also have a ring electrode disposed inside oroutside the balloon, on the balloon material, for inflated dimensions.In some embodiments, the ring may be formed of a conductive material.When a conductive ring is stretched, its intrinsic resistance mayincreases. This can be used to measure the inflated diameter of theballoon.

The electrodes placed at the distal tip of the catheter or guide wireand the electrical conductors that connect those to the electricalhardware may behave as an antenna and pick up unwanted electro-magneticinterferences from the environment that affect the integrity ofexcitation and that of measured voltages. In some embodiments, the outerjacket of the catheter or a guide wire may be used as a shield againstelectro-magnetic interference and is connected to the GND or any fixedvoltage source of the electrical hardware. Only a metallic jacket can beused as an electro-magnetic shield. In some embodiments the metallicjacket can extend along the entire length of the catheter or guide wire.In some other embodiments, the metallic jacket covers only a partialsection, while the rest of the section may be covered by a non-metallicjacket such as polymer jacket. A conductive structure may be etched onthe non-metallic jacket by the use of conductive ink, or, by any othermeans. The conductive structure may be electrically connected to themetallic jacket at the boundary edge separating the metallic andnon-metallic portion of the jacket.

Embodiments of devices, systems, and methods described herein allow apractitioner to use the catheter or active guide wire or ballooncatheter with no (or negligible) change in feel and no (or negligible)loss of ability to manipulate these devices as compared to the feel andmanipulability of similar standard devices.

A prototype 4-electrode device (electrophysiology catheter) was createdand coupled (mated) to a electrical hardware. The electrical hardwarewas coupled to a computer (standard). The electronics board compriseddata acquisition electronics, power electronics and an electrocardiogram(ECG). Multiple glass and plastic tubes having diameters varying from 3mm to 80 mm (measured using a vernier caliper) were fitted withsimulated lesions (stenoses) that were created with various materialsinserted into the tubes. The tubes with lesions were placed in salinehaving various concentrations. The device was inserted in each tubethrough each simulated lesion and the device generated electrode signalsduring the procedure that were transferred to the electronics board. Theelectronics board received the signals from the electrodes generated asthe electrodes of the device sit in the simulated vessel/lesion, and/ormove within the simulated vessel/lesion and transferred these signals tothe data acquisition module of the electronics board. Algorithms in thisembodiment were implemented on a computer to convert the signals fromthe device electrodes into various vessel measurements. The computer(algorithms thereof) determined the diameters and other measurements inreal time and created plots of the same. The results of the experimentindicated that measurement (vessel/lesion diameter) accuracy was up toabout 50 microns (micrometers).

Referring now to the embodiment comprising a first wire and a secondwire, a first terminal (i.e. emitting terminal) of the first wire may beadapted as a first electrode, in some embodiments, to receive, emit ortransmit a signal and/or current to a volume of interest, which may bepicked up (i.e. detected and/or received) by a second terminal adaptedas a second electrode (i.e. receiving terminal) of the second wire.

In one embodiment, the proximal ends of the wires are connected (i.e.coupled) to a measurement device as shown in FIG. 23. A connector may beused for connecting the proximal end of each wire to the measurementdevice.

FIG. 23 illustrates an exemplary embodiment of a diagnostic device.Diagnostic device 60 comprises excitation and measurement device 62adapted to receive the signals from at least one set of electrodes ofdiagnostic element 10 and convert (and/or transform) them tomeasurements and/or other anatomical information using processing unit64. In some embodiments, excitation and measurement device 62 mayreceive the signals from the one set of electrodes and transform them toa visual representation of the dimensions of the anatomical feature ofthe subject (the anatomical feature of interest) that are displayed ondisplay device 66. Display device 66 shows the results in differentforms, dimension values, graphical representation, or visualrepresentations overlaid on angiograms. The display device and theprocessor or part of the processor may be incorporated in a hostcomputer.

Signals may be analyzed using a data acquisition module (integrated withthe processing unit in the exemplary non-limiting embodiment) which canbe external to a standard computer, or incorporated within a standardcomputer. Processing unit 64 also incorporates one or more signalprocessing algorithms to enable the conversion of data from the measuredoutput voltage and current signals into desired anatomical measurementsor lumen dimensions as described herein.

Processing unit 64 may also be coupled to an ECG capture unit 68 andangiogram capture unit 70 for further processing. The results fromprocessing unit 64 can be overlaid on an angiographic image obtainedfrom the angiogram capture unit. The ECG data from the ECG capture unitis used in an exemplary embodiment to synchronize the lumen measurementswith angiographic images, examples of which are described below. Thusthe devices, systems, and methods described herein can provide animaging output, rather than only dimensions, and can superimpose theimage on, for non-limiting example, an angiogram or another radiographicoutput image.

FIG. 24 shows an exemplary image superimposed on a radiographic image.Overlay 250 includes two-dimensional (2D) representation 252 of a lumenprofile overlaid (or superimposed) on angiogram picture 254 of the bloodvessel 256. The measurement and processing techniques enableco-registering lumen dimension information (e.g., cross sectional area)with the positional information of the endo lumen instruments, such ascatheters or guide wires that have one or more radio opaque markers thatcan yield positional information when imaged, as is described below.These techniques are extremely useful for diagnostic guidance during amedical procedure. In some embodiments these measurements are used fordetermining a lumen trajectory in a 3D volume. Color coding may beprovided to indicate for example a healthy region by green, a suspectregion by yellow, and an alarm region by red color, other ways forproviding such added information may be used as well. These techniquesare more fully described below.

In some embodiments, the representation and angiogram picture may beprovided on a video display. Video displays may include devices uponwhich information may be displayed in a manner perceptible to a user,such as, for example, a computer monitor, cathode ray tube, liquidcrystal display, light emitting diode display, touchpad or touch screendisplay, and/or other means known in the art for emitting a visuallyperceptible output. Further in some embodiments, the visualrepresentation may be monochromatic, or may include color. In someembodiments, colors or shading may be indicative of the vesseldimensions.

In some embodiments, the representations displayed on the display devicemay include vessel dimensions along the length of the vessel or lumen.In some embodiments, the dimensions may include vessel diameter, vesselradius, vessel circumference, or vessel cross-sectional area. Thedimensions may be automatically displayed by the processing unit ontothe display unit. Alternatively, the dimensions may be displayed inresponse to a user input. Examples of user input may include, but arenot limited to, a cursor over a portion of the display (which may becontrolled by a pointing device such as a mouse, trackball, joystick,touchscreen, arrow keys, remote control), or a keyboard entry. In someembodiments, the dimensions are provided in proximity to a cursor, orother user input. For example, as a user positions a mouse cursor over aportion of the visual representation, the dimension at that portion maybe revealed. In other embodiments, all dimensions may be displayed.

In one exemplary embodiment shown in FIG. 25, measurement and excitationdevice 62 of FIG. 23 is incorporated in dongle 74 and a host computerlike a personal computer (PC) 76. The dongle 74 includes an electricalhardware that comprises signal conditioning modules 78 adapted to sendand receive a signal to and from one or more electrodes. Each signalconditioner may be coupled to a high precision circuit shown general by80 (for non-limiting example: a 16 bit data acquisition [DAQ] circuit,or an 18 bit DAQ), which converts a digital signal to an analog signaland is coupled to a level 1 signal processing unit 82. The signal maycomprise any waveform known in the art. For example, the signal maycomprise a sinusoidal waveform, square waveform, triangular waveform,saw tooth waveform, pulse waveform, or any other composite thereof.These data acquisition circuits further digitize the output voltagesmeasured by the measurement devices, and the digitized signal may beprocessed first by a level 1 signal processing unit 82. It may be notedhere that any discussion of a computer or host computer, or any specifictype of network device may include, but is not limited to, a personalcomputer, server computer, or laptop computer; personal digitalassistants (PDAs). In some embodiments, multiple devices or processorsmay be used. In some embodiments, various computers or processors may bespecially programmed to perform one or more step or calculation orperform any algorithm, as described herein

Signal processing unit 82 can be split into multiple sections, someresiding in hardware in the dongle and the rest on a host computer asshown in FIG. 25 by a level 2 signal processing unit 84. This splittingis not mandatory and in some embodiments, signal processing units 82 and84 may be incorporated entirely on the host computer, or signalprocessing units 82 and 84 may be provided entirely on a dongle. In oneexemplary embodiment, a first level of the signal processor (level 1signal processing unit) may reduce the sheer volume of data making itamenable to be transferred into a PC where the rest of the processing isdone. A level 1 or a first level signal processing unit may compress theoutput signal such that essential information is not lost, but noise isreduced in the data, thus reducing the size of the data packet (orprocessed digital signals) passed to a level 2 or second level signalprocessing unit. In one exemplary embodiment the level 1 signalprocessing unit may remove the effects of device resistance andcoupling.

The level 2 signal processor may be part of a computer or part of theelectronics board itself. This level 2 processor may execute analgorithm or a technique or a method to determine the dimensionalaspects of interest (measurements, tissue characterizations, displays ofthe same for non-limiting example). The level 1 and level 2 processorsmay be contained in a single processor which carries out both functionsof the separate level 1 and level 2 processors described. Also, at leastone of the processors and/or conditioner is configured and/or programmedto remove the effects (at least in part, if not entirely) of deviceresistance and coupling.

In one specific example the diagnostic element is incorporated into anactive guide wire, also referred to herein as a smart guide wire. In oneexample, the active guide wire may have a pair of electrode rings at thedistal end separated by a definite and unchangeable distance. In anotherexample more pairs of electrode rings may be provided. The methods ofthe invention may accommodate off-axis active guide wires, blood andtissue property variations, patient-to-patient variations (such as flow,temperature, blood chemistry, etc.), and non-isotropic tissue in thewall (i.e. localized lipid pools, thrombos, calcification, etc.).

FIG. 35 shows an example of data in the form of graphical output 258from vasculature in accordance with an embodiment of the invention. Datafrom the vasculature was created using a Finite-Element-Modeling (FEM)technique. FEM is very accurate for any given model, and models can bearbitrarily changed to assess modes of failure and limitations. FEM usescarefully calculated electrical properties of tissues. Data was createdby the FEM model, and analyzed by the algorithm (allows quantificationof errors) provided in embodiments of devices, systems and methodsdescribed herein. Pulsatile flow was also created, with lumen dimensionchanging over time. The lumen dimensions using the device werecalculated at approximately 150 times per heartbeat. This examplegenerated four times more noise than in a real in-vivo situation as achallenge to the device, system, and methods. The results indicated amaximum of 2% error (solution versus estimate) and thus, stable trackingof the lumen. In the upper plot, the top line 260 was the actual knowndimensions (radius) of the vessel across the length of the lumen(measured as a function of time). The bottom line 262 in the upper plotwas the calculated (or estimated) dimensions (radius) of the vesselacross the length of the lumen (measured as a function of time on thex-axis). The error of known dimensions versus the dimensions calculatedby the system is shown in the lower plot 264, which indicates a maximumof a 2% error for the embodiment tested.

While the initial aspect of the disclosure may focus on determiningdimensions of cardiac blood vessels, the methods can be used in otherparts of the body, in other types of other vessels or organs, and may beapplied for any other type of treatment or diagnostic applications forvarious anatomical features of a subject. For example, the methods andsystems can be used in trans catheter aortic-valve implantation (TAVI).TAVI is a procedure in which a bioprosthetic valve is inserted through acatheter and implanted within the diseased native aortic valve. For asuccessful TAVI, two critical steps include sizing of the aortic rootdiameter and thereby picking the right sent size, and determining theexact location and orientation of the bioprosthetic valve with respectto the aortic root before deployment. Sizing is typically achieved bymeans of pre-procedural echocardiographic imaging study (either TEE or3D echo). The echo is a separate procedure done in the echo lab andrequires skilled operators. The accuracy of diameter determination islimited by quality of the image and the skill and experience of the echotechnician. Currently, the position of the prosthetic valve is eyeballedangiographically and only very well trained and skilled operators areable to determine correct position. The appropriateness of the positionis decided on consensus basis between operators and experienced catheterlab nurses. Once the valve is deployed there are little to none optionsfor correction in case of erroneous placement, and furthermore theclinical repercussions are adverse. Aspects of the present technique asdescribed herein advantageously provide a guidance system that isintegrated into the current technique which can aid in sizing,positioning and deployment of the prosthetic valve.

A typical TAVI procedure begins with crossing the aortic valve by astandard 0.035″ or 0.038″ diameter J tip guide-wire through femoralartery access. A balloon valvuloplasty is typically performed by aballoon catheter to open up the stenotic aortic valve in preparation forthe prosthetic valve deployment. This step is then followed by sliding aprosthetic deployment delivery catheter in the zone of interest anddeploying the prosthetic valve. Once the valve is deployed it is checkedfor leakage (regurgitation) and function.

In one embodiment, the guidewires and methods herein determine the crosssectional area of the aortic system as it is being inserted across theaortic valve and thereby help in determination of the prosthetic size.Another embodiment for determining the accurate size involves placingelectrodes inside the balloon catheter. As the balloon is expanded forvalvuloplasty, the diameter of the balloon and hence the size of theaortic root may be determined. In yet another embodiment, the electrodesmay be placed at the tip of the valvuloplasty balloon catheters. As thetip crosses the valve the electrodes can measure the cross sectionalarea. In addition, the electrodes can also be integrated at the tip ofthe prosthetic deployment catheters (at the tip) to enhance the accuracyof placement.

FIG. 36 provides a summary of one method of measuring vascular bodilylumen dimensions. The method includes a step 268 for providing at leasttwo sets of spaced apart electrodes configured to be placed proximal toa volume of interest in vivo in a blood vessel, a step 270 for receivingan input excitation from an electrical excitation source across at leastone pair of the spaced apart electrodes placed in the volume ofinterest, a step 272 for receiving an response voltage signal from thevolume of interest from at least one set of spaced apart electrodes. Themethod further includes a step 276 for receiving an output signal at themeasurement device, wherein the output signal is a function of theresponsive voltage signal, a step 278 for measuring the output signal asa function of voltage difference between at least one set of the spacedapart electrodes; and a step 280 for converting the voltage differencesto one or more lumen dimension measurements through the varioustechniques that have been described herein.

Thus, one aspect of the disclosure provides vascular bodily lumendimensions. These methods and systems can be stand alone or they can bepart of a larger medical procedure, some examples of which are describedbelow.

Another aspect of the disclosure provides systems and methods fordetermining lumen information, such as a cross sectional area ofinterest, and tracking the movement of a diagnostic device relative tothe area of interest. Some embodiments comprise obtaining lumentrajectory information in three dimensions with respect to a particularknown reference point and also tracking the position of variousdiagnostic and therapeutic delivery devices (such as stent deliverysystems, IVUS catheters, OCT systems, or other diagnostic devicesdescribed above) with respect to the same known reference point. Themethods can therefore be used to provide precise guidance to anatomicregions of interest. Knowing the 3-D position of a diagnostic device(such as an IVUS catheter) that measures parameters such as a crosssection area of a lumen and hence regions of blockages can enablemarking the parameter (e.g., a blockage) along the 3D trajectory of thedevice on a visual device showing the lumen. Once marked, a stentdelivery system can then be guided to the marked region precisely,accurately placing the stent delivery system at the location ofinterest, in this instance the location of the blockage.

This aspect also includes methods to obtain lumen trajectory in 3D ofdiagnostic devices that pass through a vasculature, and further methodsto track the devices and stitch the parametric information measured bythe diagnostic devices with positional information obtained by theguidance system. Furthermore, a method to use the described guidancesystem to guide any endo luminal therapeutic device to points ofinterest in the vasculature is disclosed.

In one embodiment a method determines a lumen trajectory in a 3D volume.An exemplary method is shown in FIG. 37. Method 1 comprises the step ofpositioning a plurality of markers in vivo in a lumen 2. The pluralityof markers may be advantageously present on a suitable endo-lumeninstrument configured to be inserted in-vivo. “Endo-lumen instrument” asused herein includes any instrument that is adapted to makemeasurements, or observations of lumen, or provide guidance to such ameasurement or observation instrument, for example without limitation, awire, a guide wire, a catheter, etc. An exemplary wire for this purposeis a guide wire that is used to deliver stents. Other such exemplarywires may become obvious to one skilled in the art, and are contemplatedto be within the scope of the disclosure. The guidewires described abovewith electrodes disposed thereon are merely examples of markers that canbe positioned within a lumen in step 2.

Each marker is characterized by an original identity. The “identity” ofeach marker includes parameters used to identify the markers, such as aserial number of a particular marker, the position of the marker,distance from at least an end (e.g., distal or proximal end) of thedevice, distance from the closest adjacent markers, width of the marker,direction of orientation of the marker with reference to a referenceframe, etc., and combinations thereof. Markers useful in the disclosureinclude those that can become identifiable under imaging techniques orimage processing techniques. The imaging modalities known in the art arequite varied, and markers may be designed to include those that can beidentified under one or more imaging modalities. For example, one usefulmarker may be a radio-opaque material that can be imaged using X-Rays.In another exemplary embodiment, the plurality of markers may include atleast two spaced apart electrodes configured to give rise to a signalwhen excited with a pulse. In yet another exemplary embodiment, theplurality of markers may include a dye that fluoresces in the nearinfrared region of the wavelength spectrum upon suitable excitation, andhence, can be observed using an infrared spectrophotometer. Each markermay include a combination of materials to render it capable of beingobserved by multiple imaging techniques. Thus, one marker may comprise aradio-opaque material and two spaced apart electrodes. Further, theplurality of markers may include a combination of such materials. Hence,in an exemplary embodiment, one marker may comprise of a radio-opaquematerial, while another marker may be two spaced apart electrodes.

Method 1 also comprises the step of obtaining an image of the pluralityof markers 3. The manner of obtaining an image will depend on the natureof the markers involved. Subsequently, method 1 involves processing theimage 4. The processing is done to determine at least an observedidentity for each of the plurality of markers. The observed identityprovides current information of the markers in an in vivo position. Theprocessing of the image also provides an observed spacing between atleast two markers from the plurality of markers. Processing of the image4 may also be undertaken to identify other anatomical landmarks, such asidentity of the lumen near the marker, identifying cells or blockages,bifurcation of arteries, etc.

Method 1 also includes determining a position of each marker in a 3Dspace 15. The position of each marker defines a region of lumen based onthe observed identity, the observed spacing, and the original identityof each of the plurality of markers. For example, in one exemplaryembodiment, if the original identity of two markers defined by serialnumbers M1 and M2 that are spaced apart from each other by a certaindistance d1 wherein both markers are facing the same direction, and theobserved identity shows that the distance between has been reduced tod2, and one of the markers is twisted away by a certain angle relativeto the other marker, then the trajectory in 3D space between the twomarkers may be determined using mathematical techniques such asinterpolation. Mathematical techniques may be applied, such asmaintaining the same relative distance as compared to the originalrelative distance would indicate a linear path with little or no twists,while a decrease in relative distance would indicate a tortuous pathundertaken by the wire.

Method 1 further comprises determining the lumen trajectory in a 3Dvolume based on the position of each marker 6. Using the processed imagefrom step 16 and the position of each marker in a 3D space from step 5,the entire lumen trajectory in a 3D volume may be reconstructed usingtechniques known in the art, such as interpolation. Such interpolationtechniques may take advantage of the physical properties of the lumentrajectory device as well as the orientation each of the markers. Thereconstruction may be done using an appropriate computing device with aprocessor. The computing device may be a personal computer, and may becapable of providing the lumen trajectory in a 3D volume online or in anoffline manner.

FIG. 38 shows further exemplary steps 7 of some exemplary methods of thedisclosure. Step 8 comprises traversing the plurality of markers throughthe volume of interest in a lumen. The volume of interest in a lumen maybe identified from some prior information, or may be identified based onimmediate observations, such as those by an expert like a surgeon or anexperienced technician. An exemplary volume of interest may be adiseased artery. Another exemplary volume of interest may be an aneurysmin the aorta. Traversing may be achieved by known methods in the art,such as manually actuating the device comprising the plurality ofmarkers, or actuating the device using a controller mechanism such as,for example, a stepper motor.

The method 7 optionally comprises tracking the observed identity and theobserved spacing while traversing the plurality of markers, as shown instep 9. This may then be recorded as observed identity and observedspacing. Tracking the observed identity and the observed spacing may beconducted using the relevant imaging techniques, as described herein.The tracking may be achieved by obtaining a series of images at periodicintervals, and noting the time associated with each image. Alternately,if the imaging modalities allows for it (such as fluoroscopy), acontinuous image, such as a movie slice, may be obtained, and then thetracking may be done using the different frames of the movie slice.Thus, each data point extracted or obtained gives rise to an observedidentity and an observed spacing. The periodicity of obtaining image andsampling rate may depend on a variety of factors, and may include, forexample, the nature of the imaging modality, the computing power of theprocessor, the nature of information required, the condition of thelumen being observed, and the like, and combinations thereof.

An exemplary X-ray image of a guidewire G inserted through a guidecatheter C with several markers M (only four are labeled) is shown inthe left of FIG. 38A. An image analysis algorithm was run that scans theindividual pixels in each frame (picture) to identify the pixel gradeand identify those that belong to the marker and reject others that donot correspond to the markers. Discriminators can be built into thealgorithms that help the algorithm hone in on markers of interest andreject the rest of the markers that may be present in the field of view.An example of a discriminator can be the size of the marker, anotherexample can be distance between markers in a particular angle of view,yet another discriminator is the constraint that all markers are on asmooth curve. A circle was placed on identified markers in the rightside of FIG. 38A. As the guidewire traversed longitudinally through theinner diameter of catheter C a series of picture frames are generatedand the image identification algorithm identifies markers in eachpicture frame. Sequences of images in FIG. 38B show different framesobtained as the guidewire is being advanced through catheter C. Thedifferent markers were identified by the image processing algorithm ineach of the frames. Thus, the position of markers in each frame islocated. FIG. 38C shows two views of the same wire with markers. It canbe seen that in the second view, the apparent relative spacing betweenmarkers changes. For example the markers numbered 2 and 3 appear closerin the first view (on the left) even though their physical separation in3D is exactly the same. The actual physical distance between the markersis known a priori. Further, the mapping of pixels to physical distanceswas found to be about 0.25 mm per pixel in this example. Using thisinformation, the trajectory of the endolumen device can be tracked byfirst estimating the trajectory of each inter marker segment, andintegrating all the segments in a frame and then from frame to frame.

Subsequently, method 7 in FIG. 38 comprises determining a plurality ofpositions of each marker in a 3D space 11 that defines the volume ofinterest based on the observed identity, the observed spacing, and theoriginal identity of each of the plurality of markers. As alreadydescribed herein, the observed identity and observed spacing andoriginal identity and spacing may be used effectively to reconstruct alumen trajectory in which the endoluminal device traversed. Thus, themethod 7 further comprises determining the lumen trajectory in a 3Dvolume 13 based on the plurality of positions of each marker. Such alumen trajectory in a 3D volume may be determined offline from theimaging, or on a substantially real-time basis, depending on thecomputing ability available.

The positions of the markers are determined with respect to the originof each image. However, to guide other endoluminal devices after aparticular lumen trajectory is known it is essential to mark theposition of the trajectory with respect to a fixed reference.Additionally, the known size of the reference element can enablecalibration of observed markers and distances to accurate physicaldimensions. Methods herein further involve the use of a referencecomponent, such as a patch positioned on the skin of the subject that isused as a reference (origin) and calibration of all observations. Thereference component comprises at least one reference marker. In someembodiments, by virtue of its precise 2-dimensional construction, areference patch allows the mapping of the number of pixels in an imageto physical dimensions. Further, reference patches can also account formovements by the subject during measurement, which may otherwise rendermeasurements difficult to interpret. A reference patch allows for anyoffsets and deviations in measurements to be accounted for, thus givingrise to more accurate lumen trajectory in a 3D volume. The referencecomponent, such as a patch, may be present ex-vivo. In a typical usesituation, the exact position, direction of orientation, width, depthand other dimensions of the reference patch is known at all times, andthis measurement is taken along with the measurement of the at least twomarkers of the lumen trajectory device to determine the position of eachsuch marker accurately. In some instances, the reference patch may beplaced on the subject. In other embodiments the reference patch may beattached to the operating table. A reference patch may be similar to theat least two markers mentioned earlier in its composition, and may be aradio-opaque material, at least two spaced electrodes, a fluorescentdye, and the like, and combinations thereof. In one specific embodiment,the reference patch is a radio-opaque material that is capable of beingimaged using X-Ray modality. In another embodiment, the reference patchis at least two spaced electrodes. The shapes of the patch markers maybe varied to allow easier determination of orientation of the patch andhence the 2D image in relation to the subject.

Methods herein may further be used in conjunction with other techniquescurrently being used. For instance, the lumen trajectory in a 3D volumeobtained from methods herein may be overlaid onto an angiogram obtainedindependently. In another exemplary embodiment, the processing of theimage in step 4 of method 1 in FIG. 37 is done using an angiogramobtained independently and/or simultaneously.

FIG. 39 illustrates an exemplary method of use 58, wherein the method isapplied in a specific embodiment in determining actual dimensions todetermine lumen trajectory. FIG. 39 shows the endo-lumen instrument 61having two markers 63. However, one skilled in the art will understandthis principle can be extended to any number of markers on anyendo-lumen instrument, and even to multiple endo-lumen instruments, eachhaving a plurality of markers. The markers 63 are viewed by a suitableimaging modality at a particular angle, represented by numeral 65. ASstated herein, suitable imaging modality may include, for example, X-Raytechnique. The actual distance between the markers 63, represented bynumeral 67 in FIG. 39, is already known from the specification of theendo-lumen instrument, as provided by, for example a manufacturer, ormay even be made available by a suitable independent measurementtechnique. The actual distance as measured by the imaging modality 69will be different from the actual distance 67, due to angle 71 betweenthe axis of viewing by the imaging modality and the axis of the 2-Dplane of the endo-lumen instrument 63. When the apparent distancebetween two markers in 2D is less than the expected distance in a planarlayout, it can be inferred that the endo-lumen instrument is going intothe plane or coming out of the plane. The angle, theta (θ), 71 which itsubtends to the 2D plane is given by

$\begin{matrix}{{\cos (\theta)} = \frac{{Apparent}\mspace{14mu} {distance}\mspace{14mu} {between}\mspace{14mu} {markers}}{{Actual}\mspace{14mu} {distance}\mspace{14mu} {between}\mspace{14mu} {markers}}} & (4)\end{matrix}$

The actual distance 67 between two markers in a linear layout is knownin absolute terms a priori. However, all measurements made from the 2Dimage are typically viewed in terms of number of pixels on a suitableviewing medium, such as a screen. There is a need to convert thedistances measured in terms of pixels into real world dimensions (suchas millimeters). A mapping of pixels to millimeters is needed to compute3D mapping. This mapping depends upon various parameters specific to theimaging modality used, such as the picture resolution used by an X-Rayscanner, X-ray zoom factor used, and the like. In one exemplaryembodiment, the pixels to millimeters mapping can be obtained by atleast one of: (i) The zoom and picture resolution (rows & columns) ofthe X-ray image as obtained from the imaging device; (ii) Analysis ofthe 2D picture of the “reference patch” placed on any plane whose markerspacing is known a priori. By measuring patch marker distances alongrows and columns, and the angle between rows and columns, it is possibleto derive the number of pixels per actual length (for example 1 mm).

In some aspects the endoluman device is a non-elastic guidewire or othermedical device, and the methods take advantage of the nature of thenon-elastic nature of the guidewire. If a portion of the wire is trackedand found to advance or retract by a certain distance along the lumentrajectory, then the entire guidewire can be assumed to advance orretract by the same distance. Thus, even if the markers in certainregions cannot be tracked accurately due to reasons such as occlusion,interference from other objects and lack of clarity in the X-Ray image,the tracking of a subset of markers would be sufficient to estimate themovement of all the markers. If the wire is being advanced and if thedistal markers are obscured, one would not be able to determine theexact 3D trajectory of the lumen in the newly visited region into whichthe distal part of the wire is entering. However, the distance by whichthe distal markers advance into the lumen is still obtainable, and isthus clinically useful. When markers in the newly visited regioneventually become visible, the 3D trajectory of the lumen can then bere-constructed.

Another aspect of the algorithm determines the amount by which a wire orcatheter is advanced into or retracted from a lumen without necessarilyre-constructing the 3-D path of the lumen. This is done by tracking asubset of markers anywhere along the wire. Since the overall length ofthe wire of catheter does not change (since it is inelastic), the amountof advancement or retraction of any section of the wire reasonably closeto the lumen site can be reasonably approximated as the amount ofadvancement or retraction of the distal end of the wire or catheter.This result of this aspect of the algorithm is similar to other priorart techniques such as IVUS that use motorized push and pull-back todetermine the amount of advancement or retraction. Due to the elasticand compliant nature these prior art techniques are less accurate. Thisis because the movement measurements are made at the proximal end, whilethe movement required to be measured is the distal end. As the wire ispushed, the blood vessels through which the wire is inserted may stretcha little. Small changes in patient position, the heartbeat of thepatient, and the breathing of the patient are other factors that canincrease the inaccuracies of these methods. On the other hand, in thisembodiment, the markers being tracked are very close to the anatomy ofinterest, which would significantly reduce the inaccuracies. Further,additional aspects of the methods herein compensate for effects ofheartbeat to further improve the inaccuracies.

Yet another aspect of the algorithm is to estimate and compensate forthe changes in lumen trajectory due the beating of the heart. Thebeating of the heart causes a near-periodic change in the lumentrajectory. Only lumen trajectories estimated at the same phase of theheartbeat are completely consistent. Hence tracking of the lumentrajectory is done separately for different phases of the heartbeat. Atother phases, the lumen trajectory would be slightly different, butcorrelated. The effect of the heartbeat in the change in lumentrajectory is more large scale in nature. There is little local changein the trajectory, and more of overall shifts in the entire trajectory.This nature of shifting trajectory can again be modeled and estimatedfrom measurements. This approach leads to an overall improvement inaccuracy compared to determining lumen trajectory independently for eachphase of the heartbeat.

As the endo-lumen device is advanced into the blood vessel, for a givenphase of the heartbeat, the lumen trajectory is a fixed while themarkers move along the trajectory. Thus the same section of the lumentrajectory is visited by multiple markers. In other words, there is aconstraint on a marker to follow the preceding marker along a singlelumen trajectory. This can be exploited to obtain a more robust estimatefor the section of the lumen trajectory that is visited by multiplemarkers since more information is available for the section.

Method 1 can be advantageously implemented using a suitable algorithmthat works with the imaging modality in use. Fine tuning of the image todetermine the position more accurately may be done using the algorithmto obtain a very clear and accurate lumen trajectory in a 3D volume.

FIG. 40 shows a schematic of an exemplary lumen trajectory device 32.The lumen trajectory device comprises a plurality of markers 34positioned at predefined locations on wire 36 and configured to beplaced in vivo in a lumen. The spacing between each marker 38 is knownwhen all the markers are laid in a linear configuration. Other exemplarylumen devices and methods of use that can be used with the methods andsystems herein are described above.

The lumen trajectory device is typically an endo-lumen instrument onwhich the markers are disposed. In one specific embodiment, theendo-lumen instrument is a guide wire with radio-opaque markers. Inanother embodiment the endolumen instrument is a stent delivery catheterthat already has two radio-opaque markers that demarcate the ends of theballoon. In yet another embodiment the endolumen device is an IVUScatheter, known in the art, which also has radio-opaque markers that canbe tracked on an X-ray image.

In some embodiments, the markers may be in a simple band shaped form, asshown in FIG. 40. Other geometric shapes for the markers are alsocontemplated to be within the scope of the invention. In one specificembodiment, the markers are in the form of a grid pattern, comprising aplurality of smaller shapes, all of them combining to form a marker.

FIG. 41 shows lumen trajectory device 40 in a simulated method of use,wherein the device is allowed to take a tortuous path that isrepresentative of an artery (not shown). Here, it can be seen that thedistance between two markers in a linear portion 42 is similar to thespacing 38 in FIG. 40, whereas the spacing between markers 34 in thetortuous region 44 is different from that of the spacing 34 in FIG. 41.

For the reference patch, FIG. 42 shows one exemplary arrangement of onereference marker, wherein the marker is in the form of a grid pattern.

In an exemplary method of use, if the plane of viewing by an imagingmodality is perpendicular to the plane of the marker, then the imageappears as shown in FIG. 42. However, if the lumen trajectory devicetakes a tortuous path, and consequently is bent, or the viewing angle ofthe imaging modality is altered, the image appears as shown in FIG. 43,and represented by numeral 47. Since the grid covers 2 dimensions, it ispossible to determine the 3D angle of tilt of the lumen trajectorydevice. Once the tilt angle is known, it can be compensated for and usedas a reference for distances. The same patch can also be used as apositional reference to obtain orientation and bearing at any time evenwhen the imaging modality angle and region changes.

As noted herein, the image from the imaging modality is viewed on asuitable viewing medium such as a screen, wherein it appears in the formof pixels. If measured distances ‘d1’ 74 and ‘d2’ 88 are known in termsof pixels, and if angles 92 and 90 are measured, and if the actualspacing between the markers is ‘a’ (in physical dimensions such asmillimeters), the pixels per unit distance (pixels per mm) may bedetermined. Following this, using mathematical transformation involvingpitch, roll and yaw of the optical viewing modality, the measurements ofd1, d2, angles 92 and 90 may be obtained to a high degree of accuracy.In other embodiments, only one marker may be used on the referencepatch. In this case, the apparent shape of the marker would depend onthe angle from which it is viewed. By measuring the apparent dimensionsand the angular orientation of the shape itself, it viewing angle aswell as the pixels per unit distance may be determined. Using moremarkers improves the robustness of this determination. As such, it is tobe understood that one or more markers may be used for the referencepatch.

When the apparent distance between two markers in 2D is less than theexpected distance in a planar layout, there is an ambiguity betweenwhether the endo-lumen instrument is going into the plane or coming outof the plane. In such cases, parameters specific to the volume ofinterest such as anatomical information as well as the lumen trajectorydevice parameters such as smooth continuity constraints of theendo-lumen instrument can be used to resolve the ambiguity.

The lumen trajectory device of the invention 23 further comprises areference patch. The reference patch may be present at a pre-determinedposition place ex vivo in the field of view of an imaging device usedfor imaging the lumen trajectory device. In some embodiments, thereference patch comprises of one or more calibration electrodes arrangedin a pre-determined pattern, wherein in one exemplary embodiment, thepre-determined pattern is a grid pattern. FIG. 44 shows anotherexemplary arrangement of a reference patch 81 on the lumen trajectorydevice of the invention, wherein the markers are in the form of a gridpattern, and the pattern comprises one shape 83 that is different fromthe rest of the shapes at a particular position on the grid, such thatby viewing it using suitable imaging means, the orientation of themarker with respect to the viewing plane may be determined in a facilemanner.

In a further use of the lumen trajectory device of the invention, afterthe 3D trajectory of the lumen is generated using a lumen trajectorydevice, then it is feasible to register and determine the exact positionof any device that has markers (radio-graphic or otherwise) that can beidentified using an imaging modality. Such determination of uniqueposition of the device is feasible either in the presence of the lumentrajectory device in the field of view by tracking relative positionswith respect to fixed and known positions of the lumen tracking device.Alternately, in the absence of the lumen trajectory tracking device, theunique position of the device may be determined by utilizing thereference patch as a common reference. Co-registering is described inmore detail below.

In a yet another embodiment, the lumen trajectory device may be used toobtain more accurate renditions of the 3D trajectory of the lumen volumeof interest. This may be achieved by inserting the endo-lumen instrument(by either pushing or pulling it) through the lumen during which time,different sets of markers occupy the same region in the lumen. Thisaffords multiple measurements of the 3-D trajectory for the same region.These multiple measurements can be used to further refine the lumen 3Dand make it more accurate. These multiple measurements can also be usedto determine the 3D trajectory of lumen segments corresponding tomultiple phases of the heartbeat.

In yet another aspect, the invention provides a lumen trajectory system.Referring to the drawings, FIG. 45 shows a block diagrammaticrepresentation of the lumen trajectory system 53. The system comprises aplurality of markers 55 positioned at predefined locations on a wire orother endoluminal device. As already noted, the device is configured tobe placed in vivo in a volume of interest. The system comprises animaging component 57 for imaging the endoluminal device in the volume ofinterest in a lumen as it traverses the lumen. Imaging may include, forexample, but not limited to, X-Ray, infrared, ultrasound, and the like,and combinations thereof. The imaging component 57 is configured toobtain an image of the wire at different time intervals as the trackingmodule traverses through the volume of interest, to provide the observedidentity the observed spacing. The imaging component 57 is furtherconfigured to behave as a synchronous phase imaging device to obtainphase synchronized images, so as to map the observed identity atdifferent phases of heart.

The lumen trajectory system 53 also comprises a processing component 56.The processing component is used for processing the image obtained fromthe imaging component to determine at least an observed identity foreach of the plurality of markets and an observed spacing between atleast two markers from the plurality of markers. The lumen trajectorysystem 53 uses the method described herein to determine at least anobserved identity for each of the plurality of markers and an observedspacing between at least two markers from the plurality of markers. Thelumen trajectory system 53 is further used for determining a position ofeach marker in a 3D space that defines the volume of interest based onthe observed identity, the observed spacing and an original identity ofeach of the plurality of markers, to determine the lumen trajectory in a3D volume based on the position of each marker, using the method stepsof the invention described herein.

The lumen trajectory system also comprises a reference patch tocalibrate the observed data from the imaging means and the processingmeans. The reference patch may be configured as already describedherein.

The lumen trajectory system 53 may also comprise an output module toprovide the results and image as a suitable output. Typical outputincludes a 3D static image, an animated rendition of the lumentrajectory, and the like. The lumen trajectory system further comprisesa communication module to communicate the results and image to suitablerecipients, such as experts, physicians, specialists, and the like.Wireless and wired communication may be possible depending on thecomputing capability, bandwidth, file size, and the like. Othercomponents and features relevant to the lumen trajectory system of theinvention 53 will become obvious to one skilled in the art, and iscontemplated to be within the scope of the invention.

Some embodiments provide for obtaining reference information fordiagnostic guidance for an in vivo medical procedure. FIG. 46 showsexemplary steps involved in exemplary method 140. The method comprisesproviding lumen trajectory information corresponding to a lumen in step142. Lumen trajectory information can be obtained as described in any ofthe methods herein above. Lumen trajectory information may also beobtained from a variety of techniques known in the art, and may include,for example, but not limited to, MRI, X ray, ECG, fluoroscopy,microscopy, ultrasound imaging and combinations thereof. Depending onthe technique used to obtain the lumen trajectory information and thecomputing power available on hand, the lumen trajectory information maybe a 2D image, a 3D image, in a tabular form, or any other suitable formof representation. In one specific embodiment, when the lumen trajectoryinformation is provided in a tabular form, the table may comprisecolumns such as Serial Number, Distance from a Reference Point (such asthe insertion point of a catheter), and the like. Data points madeavailable in a tabular form may have the appropriate levels ofexperimental accuracy as required, such as ±0.01 mm.

The method then comprises providing parametric information correspondingto the lumen in step 144. Parametric information includes anyinformation that gives an idea on the nature of the lumen, such as, forexample without limitation, pressure, blood flow rate, cross sectionalarea, and combinations thereof. This type of information may benecessary to assess blocks, aneurysms, stenosis, and the like, andcombinations thereof. Such information is obtained from any of severaltechniques, and may include for example, at least one of a microscopy,ultrasound, Intra Vascular Ultrasound (IVUS), Near Infrared spectroscopy(NIR), Optical Coherence Tomography (OCT), vascular optical camera typedevices, other lumen measuring devices described above, and otherendo-lumen diagnostic devices, and any combinations thereof. Theexemplary techniques may further require the use of endo-lumeninstruments as described herein.

The lumen trajectory information and the parametric information may besimultaneously obtained or they may be independently obtained. Dependingon how and when the lumen trajectory and parametric information wereobtained, combining the two kinds of information is done using severaltechniques. One such technique is to time stamp the image and use thesame clock to time stamp the parametric measurements from the endoluminal instrument. Since the position information of the endoluminaldevice obtained through image processing technique described in thisapplication has the same time stamp as that of the diagnostic parametricvalue (e.g., cross sectional area, pressure etc) the two can be stitchedto form the reference information. Another method of stitching theparametric measurements with the position information is to use ECGgating. ECG is done as a routine step for all interventions. The 3Dposition information of the endolumen instrument is obtained from theimaging modality (e.g., X-ray) and the parametric information from thediagnostic endo luminal can be ECG gated and therefore stitched togetherin time domain to provide reference information.

The method further comprises combining the lumen trajectory informationwith the parametric information to obtain the reference information fordiagnostic guidance in step 146. The combination of lumen trajectoryinformation and the parametric information may be made available in animage form, a tabular representation, or any other visualrepresentation, and combinations thereof. Thus, in one exemplaryembodiment, the reference information is made available as an image oflumen trajectory information on which text of parametric information isoverlaid. In a specific embodiment, the reference information is a fullycolored image, wherein the choice of colors is an indication of certainparametric information. In another embodiment, the parametricinformation may be displayed as different shades of the same colorindicating the degree of variation of the parameter along the lumentrajectory. In yet another embodiment, the reference information is ananimation. The reference information made available as an image and/oranimation may be of a suitable resolution to allow for facile diagnosisand/or treatment, or whatever the medical procedure is expected toachieve. Resolution may be measured in terms of minimum distance thatneeds to be distinguishable within the lumen.

In another exemplary embodiment, the reference information is madeavailable in tabular form, wherein the columns include headers such as,but not limited to, Position ID, distance from reference, crosssectional area at the particular distance, and so on. It will becomeobvious to one skilled in the art that, for example, in the tabularrepresentation, not all distances from reference may have associatedparametric information like cross sectional area, whereas only certainpositions will have the associated parametric information. The exactnature of the reference information will depend on various factors, suchas but not limited to, the medical procedure requirement, availablecomputing capabilities, operator's comfort and preference, and the like.

Once such reference information is made available in a suitable form, itcan then displayed on a graphical user interface to be viewed having acertain suitable minimum resolution (as measured in, for example,pixels) and used by medical personnel. Such reference informationprovides for better identification of regions of interest and can beused to guide therapy devices more accurately to the target region. Whenthe reference information is made available in a graphical userinterface, inter-active capabilities such as zooming in and zooming outof the image can also be made possible, to enable a medical personnel tozoom into a region of interest within the lumen, and zoom out to viewthe entire lumen as a whole, or perform other suitable actions ofrelevance to enable effective diagnosis and/or treatment.

In some embodiments, while obtaining lumen trajectory information andparametric information, it may be useful to include a fixed referencefor a field of view. Such a fixed reference for a field of view accountsfor variations during the measurements and observations made atdifferent times, or the movement by a subject, or any such differencesarising due to extraneous circumstances. This allows for combining ofthe lumen trajectory information and the parametric information whileaccounting for all the variations and differences and still providesaccurate reference information. In the absence of such fixed referencefor the field of view, the error corrections due to variations fromextraneous circumstances can only be corrected based on operator ortechnician or medical personnel's skill and experience. Fixed referencefor the field of view may be obtained by a variety of techniques, andinclude, for example, attaching a radio opaque marker patch having knowndimensions at a particular position on a subject; attaching a radioopaque marker patch on an object that may be outside the subject; aninitial marking of at least one anatomic location in the lumentrajectory information by a user, wherein the characteristics of theanatomical location is known beforehand from other techniques; using aset of co-ordinates of an imaging system, such as a CNC co-ordinates ofan X-ray machine. It would be appreciated by those skilled in the artthat it is useful to allow users to allow the flexibility of identifyingcertain anatomical landmarks (e.g., beginning and end of lesions, valveroot, bifurcations etc.) along the lumen trajectory.

In a further embodiment, the reference information comprises areas ofdiagnostic interest that are marked. For example, medical personnel canidentify particular points of interest along the trajectory that theywant to keep track of when subsequently delivering a therapy device suchas, for example, a bifurcation. These areas of diagnostic interest mayrepresent any particular condition of the lumen, such as blocks,stenosis, aneurysms, and the like, and combinations thereof. The one ormore markings may be made by relevant personnel, such as a medicalpractitioner or a technician or a specialist, as a particular situationdemands. Such markings allow for greater ease of diagnosis and treatmentof the subject. The markings can be made by physically identifying aregion of interest on a screen using, for example, a touch screen or amouse.

In some embodiments, the lumen trajectory information and parametricinformation are phase synchronized. The heart has phases that includepumping and back-filling, also referred to as systole and diastole.During each phase, the nature of the lumen changes as compared to thenature of the lumen in another phase. Thus, in some instances, it isimportant to know the phase of the heart while obtaining the lumentrajectory information and the parametric information. Methods ofidentifying the phases of the heart are known in the art, such aselectrocardiogram (ECG). For example, obtaining lumen trajectoryinformation and parametric information may be achieved along with ECGgating to ensure phase synchronization. Multiple measurements with ECGgating may be necessary to obtain a good average measurement that isviable for further use.

Having such accurate reference information on hand provides a distinctadvantage for the medical personnel to conduct diagnosis, treatsubjects, perform surgeries, and conduct any medical procedures withgreater chances of success. Thus, medical personnel do not have to relyon skill, expertise, knowledge and experience in the field entirely toperform a medical procedure. The reference information made available bythe method of the invention will augment a medical personnel's skill,knowledge, experience and expertise very well.

Another aspect is a method for guiding an endo-lumen instrument in thelumen using the reference information. The exemplary steps for thismethod are shown in FIG. 47 in the form of flowchart 148. The referenceinformation is obtained as described herein above. The method forguiding the endo-lumen instrument involves imaging the endo-lumeninstrument after it has been inserted into the lumen to provide anendo-lumen instrument image, depicted by numeral 150. Techniques forimaging are known, and may include, X-Ray, MRI, etc. The image is madeavailable as a 2D image or may be represented in any convenient formsuitable for viewing. The convenient form may depend on a variety offactors, such as computing requirements, ease of viewing andcomprehensibility, medical personnel's comfort level, and the like, andcombinations thereof.

Further, the endo-lumen instrument image may also ECG based bysynchronizing the imaging technique with cardiac gating. The method forguiding the endo-lumen instrument then includes correlating theendo-lumen instrument image with the reference information, shown bynumeral 150. As noted herein, the reference information may be in anysuitable form, and the endo-lumen instrument image will also beconverted into a suitable form such that the endo-lumen instrument imageand the reference information may be correlated appropriately. In oneembodiment, the reference information is made available as a 2D staticimage, and the endo-lumen instrument image is also made available as a2D image overlayed in realtime along the lumen trajectory as theendolumen instrument traverses the path, thus the instantaneous positionof the endo-lumen instrument with respect to the reference informationof the lumen. One skilled in the art will immediately recognize that aseries of such correlations may be performed to obtain almost areal-time sequence of endo-lumen instrument images with respect to thereference information, thus guiding the endoluminal instrument to thedesired position of interest within the lumen.

Subsequently, any endo-lumen instrument is guided to the region ofinterest, as shown in step 154. Guiding may be achieved in a facilemanner using methods described herein. Thus, in an exemplary embodiment,the reference information is made available as a 2D reference image, andthe endo-lumen instrument image is tracked with respect to the referenceimage. This is then displayed on a graphical user interface such as ascreen having suitable resolution, such as 1024×800 pixels. Medicalpersonnel can then view the endo-lumen instrument as it traversesthrough the lumen, and then arrive at a region of interest that isdisplayed in a clear manner on the reference image (along the lumentrajectory originally generated). As noted herein, one or more regionsof interest (lesions, bifurcations, vascular anomalies etc.) in thelumen along the trajectory may also be marked and registered withrespect to the “same” fixed reference (origin) as of the lumentrajectory to allow for conducting the medical procedure in a facilemanner. The medical personnel may also be given the ability to zoom intoa region of interest to allow for accurately guiding the endo-lumeninstrument to the exact position to conduct any medical procedures. Suchmedical procedures may include, for example, delivering a stent,delivering a balloon catheter along with the stent, etc.

Methods herein can be advantageously administered using a suitablesoftware program or algorithm. Thus, in yet another aspect, thedisclosure provides algorithms for obtaining reference information andthe method for guiding an endo-lumen instrument. The algorithm(s)generally require certain minimum computing requirements with processingcapabilities that are also connected appropriately to the imaginginstrument to process the images that come from the instrument. Asuitable graphical user interface, such as a screen having a certainresolution, input/output interfaces such as keyboard and mouse can beused with the algorithm. The algorithm can be on a suitable medium suchas a CD, a flash drive, an external hard drive, EPROM, and the like. Thealgorithm can be provided as a downloadable program in the form of anexecutable and self-extractable file from a suitable source, such as awebsite on the internet.

In a further aspect, a system is adapted to guide the endo-lumeninstrument to a region of interest in the lumen. FIG. 48 in a blockdiagrammatic representation of exemplary system 156. System 26 comprisesa first means 158 for providing the lumen trajectory information, whichmay include any of the techniques described herein; a second means 160for providing a parametric information, an imaging means 162 to imagethe endo-lumen instrument in the lumen for obtaining an endo-lumeninstrument image, a first processor 164 for combining the lumentrajectory information and the parametric information to provide areference information, and a second processor 166 for correlating theendo-lumen instrument image with the reference information to guide theendo-lumen instrument to the region of interest in the lumen. The systemmay also comprise a display module to display the reference information,the endo-lumen instrument image, and combined reference information andendo-lumen instrument image. The system also comprises an input/outputmodule, where the input module receives inputs for the first means andsecond means and the output module provides the results for the firstand second processor. The system also comprises a communication moduleto enable communication between the various modules. The manner ofcommunication may be through wired connections, such as using IEEE 488cable, RS-232 cable, Ethernet cable, telephone line, VGA adapter cable,and the like, and combinations thereof. Alternately, communicationsbetween various module may be achieved wirelessly, such as usingBluetooth, infrared connectivity, wireless LAN, and the like. Furthermodules that may be incorporated into the system will become obvious toone skilled in the art, and is contemplated to be within the scope ofthe invention. The individual modules may also be situated remote toeach other and connected through appropriate means to each other. Thus,the display module may be made available in a remote location, such asin another part of the building, or in a different location in the city,and so on, where, for example, an expert is located, to obtain theexpert's opinion and guidance while conducting the medical procedure.

A hypothetical example is now provided to illustrate an exemplary methodthat obtains vascular bodily lumen information and uses it to guide atherapy device within the lumen to a region of interest. A 65 year-oldsubject having hypertension, dyslipidemia, a prior catheterization, andexhibiting mild coronary artery disease, markedly abnormal nuclearstress test, and a large wall defect. Although asymptomatic, the patientis referred for cardiac catheterization, given large perfusion defect.Angiography reveals a 95% stenosis. Using traditional stentingtechniques, post-stenting angiography reveals a question as to whetherthe stent is optimally deployed since the vessel appears to neck downproximal to the stent. Post-stenting IVUS reveals the stent issignificantly undersized and underexpanded. A repeat intervention isrequired, and a second stent is deployed proximal to the first stent.

This repeat intervention could be avoided using the exemplary method.With standard angiography aided by IVUS, the steps of the interventioninclude performing the angiography; stent selection based onangiographic visual assessment (subjective due to foreshortening andvisual artifacts); intervention (stent placement and deployment)followed by angiography that reveals potential for suboptimal deployment(geographic miss). To confirm this, IVUS is used to reveal the stent isundersized and/or underexpanded and/or longitudinally misplaced. TheIVUS catheter is replaced by another dilation catheter and the stent ispost-dilated to correct for undersizing. The dilation catheter isreplaced by a stent catheter and a second stein is placed proximal tothe first stent (and/or overlapping). A final angiography is performedto confirm results. Due to time, a second IVUS review of the stents mayor may not be performed, leaving some uncertainty in the process as tothe success of the procedure. Thus, as outlined several exchanges ofdevices have to be made to achieve the result. Furthermore, the exactposition of the lesion is not known in real time and hence the stentdelivery catheter cannot be guided to the right location leaving roomfor longitudinal geographic misplacement of stent.

In contrast, when a guidewire with electrodes as described above is usedfor the catheterization procedure, the process is simplified. First anangiography is performed; a guide wire as described above is positionedin the vessel across the lesion; the system obtains lesion lengthmeasurements and/or reference vessel diameter and/or cross sectionalarea as it traverses through the lesion using techniques describedherein. Concomitantly, as the guidewire is traversing the lumen, thepositional information of the guidewire and other anatomic points ofinterests such as lesions and bifurcation are co-registered with respectto a fixed reference, which is described above. The cross sectional areainformation is stitched with the position information to create aguidance system as described above. Based on the cross sectional area ofthe lesion, the minimum lumen area (“MLA”) of the lesion, and the lengthof the lesion, the physician selects an appropriate Stent fordeployment. The location of the lesion can be overlayed on a staticreference angiographic image that is used by the physician to guide thestent delivery catheter to the correct location. Furthermore, since thestent delivery catheter has radio-opaque markers it can be tracked withrespect to the same reference as that of the active guide wire using theimage processing algorithms described above. In one of the embodimentsof the system interface a rendering of the stent delivery cathetermovement can be displayed on the same static angiographic image that hasan overlay of lesion location. Thus, this gives the physician precisevisual representation of location of the stent with respect to thelesion in real time. Once the stent is deployed in the location ofinterest the stent delivery catheter can be withdrawn back behind thestented zone. The guide wire can then be retracted back such that theelectrodes cross the stented region. As the electrodes cross the stentedzone they provide a measurement of cross sectional area of the stentedzone, i.e. a complete stent profile. By comparing this to the referencelumen (i.e., not blocked) cross sectional area, it can be determined ifthe stent is under-deployed. If so, the user can either advance the samestent delivery system to the precise location and expand again, or theycan formulate their post-dilation strategy using the measuredinformation. If the physician chooses to post dilate, then the size ofthe post dilation balloon catheter is precisely determined using theinformation on the stented cross sectional area profile and thereference lumen cross sectional area, thus, mitigating post dilationinjury. The final stent profile and cross sectional area after postdilation can be also measured by retracting the guidewire. Therefore,the guidewire can be used to measure cross sectional area, guide thechoice of stent, precisely place and deploy the stent, and guide thepost deployment strategy and verification of therapy. All this can beachieved without exchanging various tools, as is required in IVUS guidedor angiographically guided procedures. This makes the overall proceduresimple, less time consuming, cost effective, and beneficial to thepatient.

An additional example now illustrates how the guidance system asdescribed above can be used with existing imaging modalities for stemplacement. A physician would have a choice to place the stent using IVUSor OCT guidance, traditional angiography guidance, OR guidance throughthe use of the described endoluminal guidance system described above.

In an IVUS/OCT guided system the IVUS/OCT device would be introduced inthe vasculature across the point of blockage shown by the angiography.Then, using a motorized pull back the IVUS/OCT catheter is pulled backat a known fixed rate while the parameters such as lumen cross sectionalarea are recorded. Based on the information an appropriate stent size isselected. The IVUS/OCT system is then retracted from the vasculature andthen exchanged for the stent delivery catheter. While the IVUS/OCTsystems provide information about the lesion they provide no positionalinformation of the measurements. That is, the measurements do notindicate the location of the measurement and therefore offer onlyinformation to select appropriate stent size but no further guidance towhere the stent should be positioned. This is a significantdisadvantage. The stent delivery catheter is then advanced to the pointof interest and positioned in place by visually estimating the stenoticregion on the previously-obtained still angiographic image. Theangiographic images are 2D and suffer from foreshortening effects andare subject to gross errors in case of tortuous vessel. This is a verywell-known phenomenon and the physician has to rely only on his or herown experience and skill. This technique can render the stents beinggeographically misplaced longitudinally (i.e., the expanded stem doesnot cover the entire blockage). This can only be verified by retractingthe stent delivery catheter from the subject and repeating an IVUS/OCTimaging. If found misplaced, a possible remedy is to expand another stemin place, thus adding significant procedural cost, time and patientrisk, or alternatively perform other interventions such as using apost-dilation balloon to expand in the non-covered section which isknown to cause complications such as stent edge dissections that haveserious consequences.

In a non IVUS/OCT guided procedure the physician selects the stem sizebased on experience (subjective and prone to errors). The stent deliverycatheter is then advanced under X-ray view and the position of the stentin relation to the lesion is visually estimated as described previously.This method again suffers from the same drawbacks as the IVUS/OCT guidedtechnique described above and is prone to longitudinal geographical missand its associated effects (additional cost, time, complexity, andpatient risk).

When the aforementioned guidance system is used in conjunction withIVUS/OCT or other diagnostic devices as described above (referred toherein as the “measurement device”) the procedure is much simplified andless prone to geographical miss. First, the measurement device isadvanced through the lumen across the lesion of interest to measureimportant lumen parameters such as lumen cross sectional area that helpdetermine the appropriate size of the stent to be used as the devices.Concomitantly, as the measuring device is traversing the lumen, the 3Dpositional trajectory information of the device is obtained using theimaging modality and techniques described above. Hence, the lesion isco-registered respect to a fixed reference and its 3D position along thelumen trajectory is registered. Additionally, the user has an option tomark anatomic points of interests such as bifurcations or otherlandmarks along the lumen trajectory and they are co-registered withrespect to the same fixed reference. The parametric information (Such ascross sectional area) collected by the measurement device is stitchedwith the position information thus obtained via one of the techniquespreviously described. One of the advantages is that all of this happensin real-time. The location of the lesion can be overlayed on the staticreference angiographic image that is used by the physician to guide stemdelivery catheter to the correct location. Note that the user hascompleted only one step so far of advancing the measurement devicesacross the lesion. Now the measurement instrument is retracted if it isan IVUS or OCT system, or left in place if it is a guidewire asdescribed above. The stent delivery catheter is then advanced into thevasculature. Since the stern delivery catheter has radio-opaque markersit can be tracked with respect to the same fixed reference using similarimage processing algorithms described above. In one of the embodimentsof the system interface a rendering of the stern delivery cathetermovement can be displayed on the same static angiographic image that hasan overlay of lesion location. Thus this gives the physician precisevisual representation of location of the stent with respect to thelesion in real time. Thus, this technique provides necessary guidance toposition the stent accurately and minimizes room for subjectivity anderror while not introducing any additional steps. Potential benefits ofthe guidance system are immense as it may help in avoiding repeatintervention (additional stent), reduce cost, procedural time, andsubject the patient to less risk.

In the embodiments above, the measurement and the excitation apparatusare at a physical distance from the sensors or the load across whichthese measurements are desired. Conductors, as described above,typically connect the electrical source, measurement apparatus, and theload, forming an electrical network. It may be appreciated by thoseskilled in the art that electrical de-embedding would be needed toobtain the voltage-current distributions found at the distal end wherethe electrodes are located based solely on the actual measurements thatare performed at the proximal end of the guide-wire or catheter. Thismay include taking into consideration material properties of thedevices, or device components, such as the wires or electrodes.Measurements may be calibrated to take such variations into account toyield accurate and precise measurements. De-embedding may occur forsystems with any number of terminals, e.g., 2 port, 4 port, or any othernumber. Electrical values (e.g., voltage, current) may be transformedbetween the distal end and the proximal end of the diagnostic element asdescribed herein.

There are many types of parameters known in the art for modeling anelectrical network. For example, Z parameters, also called the impedanceparameters of a network, relate the voltage and currents of a multi-portnetwork. As an example of a 2 port network, with reference to FIG. 49,the 2 voltages and 2 currents are related by Z parameters as follows:

$\begin{matrix}{{\begin{pmatrix}V_{1} \\V_{2}\end{pmatrix} = {\begin{pmatrix}Z_{11} & Z_{12} \\Z_{21} & Z_{22}\end{pmatrix}\begin{pmatrix}I_{1} \\I_{2}\end{pmatrix}}}{{{Where}\mspace{14mu} Z_{11}} = {\left. \frac{V_{1}}{I_{1}} \middle| {}_{I_{2} = 0}\mspace{14mu} Z_{12} \right. = {\left. \frac{V_{1}}{I_{2}} \middle| {}_{I_{1} = 0}\mspace{14mu} Z_{21} \right. = {\left. \frac{V_{2}}{I_{1}} \middle| {}_{I_{2} = 0}Z_{22} \right. = \left. \frac{V_{2}}{I_{2}} \right|_{I_{1} = 0}}}}}} & (5)\end{matrix}$

For the general case of an n-port network, it can be stated that

$\mspace{14mu} {Z_{nm} = \left. \frac{V_{n}}{I_{m}} \right|_{I_{n} = 0}}$

Y parameters, also referred to as Admittance parameters of a network,also relate the voltage and currents of a multi-port electrical network.As an example of a 2 port network, the 2 voltages and 2 currents arerelated by Y parameters as follows

$\begin{matrix}{{\begin{pmatrix}I_{1} \\I_{2}\end{pmatrix} = {\begin{pmatrix}Y_{11} & Y_{12} \\Y_{21} & Y_{22}\end{pmatrix}\begin{pmatrix}V_{1} \\V_{2}\end{pmatrix}}}{{{Where}\mspace{14mu} Y_{11}} = {\left. \frac{I_{1}}{V_{1}} \middle| {}_{V_{2} = 0}\mspace{14mu} Y_{12} \right. = {\left. \frac{I_{1}}{V_{2}} \middle| {}_{V_{1} = 0}\mspace{14mu} Y_{21} \right. = {\left. \frac{I_{2}}{V_{1}} \middle| {}_{V_{2} = 0}Y_{22} \right. = \left. \frac{I_{2}}{V_{2}} \right|_{V_{1} = 0}}}}}} & (6)\end{matrix}$

S parameters, also called the Scattering parameters of a network, relatethe incident and reflected power waves. The relationship between thereflected power waves, incident power waves and the S-parameter matrixis given by:

$\begin{matrix}{\begin{pmatrix}b_{1} \\b_{2}\end{pmatrix} = {\begin{pmatrix}S_{11} & S_{12} \\S_{21} & S_{22}\end{pmatrix}\begin{pmatrix}a_{1} \\a_{2}\end{pmatrix}}} & (7)\end{matrix}$

where a_(n) and b_(n) are the incident and reflected waves,respectively, and are related to the port voltages and currents.

H parameters, also called the Hybrid parameters, relate the portvoltages and currents in a different way. For a 2-port network:

$\begin{bmatrix}V_{1} \\I_{2}\end{bmatrix} = {\begin{bmatrix}h_{11} & h_{12} \\h_{21} & h_{22}\end{bmatrix}\begin{bmatrix}I_{1} \\V_{2}\end{bmatrix}}$${{Where}\mspace{14mu} h_{11}}\overset{def}{=}{\left. \frac{V_{1}}{I_{1}} \middle| {}_{V_{2} = 0}\mspace{14mu} h_{12} \right.\overset{def}{=}{\left. \frac{V_{1}}{V_{2}} \middle| {}_{I_{1} = 0}\mspace{14mu} h_{21} \right.\overset{def}{=}{\left. \frac{I_{2}}{I_{1}} \middle| {}_{V_{2} = 0}h_{22} \right.\overset{def}{=}\left. \frac{I_{1}}{V_{2}} \right|_{I_{1} = 0}}}}$

G parameters, also called the inverse Hybrid parameters of a network,relate the voltages and current as follows:

$\begin{matrix}{{\begin{bmatrix}I_{1} \\V_{2}\end{bmatrix} = {\begin{bmatrix}g_{11} & g_{12} \\g_{21} & g_{22}\end{bmatrix}\begin{bmatrix}V_{1} \\I_{2}\end{bmatrix}}}{{{Where}\mspace{14mu} g_{11}}\overset{def}{=}{\left. \frac{I_{1}}{V_{1}} \middle| {}_{I_{2} = 0}\mspace{14mu} g_{12} \right.\overset{def}{=}{\left. \frac{I_{1}}{I_{2}} \middle| {}_{V_{1} = 0}\mspace{14mu} g_{21} \right.\overset{def}{=}{\left. \frac{V_{2}}{V_{1}} \middle| {}_{I_{2} = 0}g_{22} \right.\overset{def}{=}\left. \frac{V_{2}}{I_{2}} \right|_{V_{1} = 0}}}}}} & (8)\end{matrix}$

All the above formulations are related, and one set of parameters can bederived from another. These formulations are well known and establishedin the art. The Z and Y parameter matrices are inverses of each other.The H and G parameter matrices are inverses of each other. The Y and Sparameters are also related, and can be derived from each other. All ofthe mentioned types of models are electrically equivalent. The choice ofimplementation depends on convenience and specific needs of a problem.

In some of these electrical networks, measurements taken for a distantload need to account for the electrical losses and coupling andcompensate for any parasitic effects of electrical networks formed atthe electrical source, measurement apparatus and the conductors. Thisproblem has been dealt with extensively for a single load, situatedremotely and connected across a pair of conductors that connects to anexcitation and measurement apparatus disposed at a proximal location. Itis a commonly used technique in high precision measurements and ispopularly referred to as “Port Extension.” Such a network is generallymodeled as a two port network and the network parameters are solved bymeasuring proximal parameters for known distal loads. Nodal analysis,Mesh analysis, Superposition methods have been proposed to solve linearelectrical networks. Transfer functions have also been proposed for twoport networks.

However, few solutions exist when the load is not a simple single loadbut a distributed network with multiple ports forming a load network.Such systems have multiple conductor wires and multiple measuremententities. Therefore there exists a need to accurately measure electricalproperties across a distant multi-port load network.

De-embedding is a process that may include taking into considerationmaterial properties of the devices, or device components, such as thewires or electrodes. For example, an electrode may be at a distal end ofa wire at the region of interest, and electronics to receive and processthe signals may be provided at a proximal end of a wire. An electricalmeasurement taken by the distal electrode(s) is received by theelectronics. However, a signal provided at one end of the wire may bealtered by the time it reaches the other end of the wire due to materialproperties of the wire. This variation may be taken into account byusing appropriate models based on the material characteristics, lengthof the wire, and other variables relevant to this situation, orperforming measurements with known electrical loads at distal end andcalibrating the effect of the in between electrical conductors.

For all ports the output voltages may be defined in terms of theZ-parameter matrix and the input currents by the following matrixequation:

V=Z*I

where Z is an N×N matrix the elements of which can be indexed usingconventional matrix notation. In general the elements of the Z-parametermatrix are complex numbers and functions of frequency. For a one-portnetwork, as will be clear to one skilled in the art, the Z-matrixreduces to a single element, that is the ordinary impedance measuredbetween the two terminals.

An equivalent relationship between port voltages and currents of anN-port network can also be expressed as

I=Y*V

where Y is an N×N matrix. Y is related to Z, and generally speaking, isthe matrix inverse of Z. In some special circumstances, either Z or Ybecomes non-invertible.

FIG. 50 is a diagrammatic representation of an exemplary embodiment ofsystem 171. The system is adapted to estimate electrical network 174 ofa distant zone (herein referred to as a load network) when it is excitedby an electrical stimulus near the proximal end. Load network 174situated on the distal end is connected to a plurality of stimulatingand measuring devices 170 on the proximal end through a plurality ofconductors 172 whose combined electrical property is fixed but unknown.The stimulus can be either an arbitrary current or voltage from theexcitation device located at the proximal end while the measurements arein the form of voltage measurements again at the proximal end. Thevoltage measurement is in general non-ideal (i.e., the voltagemeasurement devices draw non-zero finite currents from the network andhence loads the network). As would be appreciated by those skilled inthe art, the systems and methods described herein can be extended andapplied to any area of operation where the electrical network to beestimated is situated at a remote location where in-situ excitation andmeasurements are not feasible.

It would be understood by those skilled in the art that for an n-portload network, there would be multiple conductor wires (up to n pairs)extending down to the proximal end connecting to an excitation entityand at least to corresponding “n” measurement entities. An additionalreference measurement is also performed across two arbitrary nodes inthe circuit, such that it has independent information from the previousn measurements.

An exemplary method of using system 171 from FIG. 51 is shown in FIG.52. System 171 measures voltages at the proximal end corresponding todistal voltages across four conductors connected to the distal endelectrodes 188 (four shown) placed in vivo in a body lumen 190. Thesemeasurements are useful for estimating the lumen dimension, which inturn is useful for several medical procedures. As shown, the fourelectrodes 188 are disposed longitudinally on distal region 192 ofelongate medical device 194, such as a catheter or a guide wire.Elongate medical device 194 has been positioned within lumen 190 of avascular bodily lumen, such as a blood vessel. The four electrodes areelectrically coupled to four conductors 198 extending along the lengthof the elongate medical device 194, and terminating on a connector onthe proximal end 196. Though four electrodes are shown for the exemplaryembodiment, three or more electrodes can be used in differentconfigurations needed for measurements and these are included in thescope of the systems and methods described herein. The connector iselectrically connected to hardware adapted to provide the stimulusacross the two conductors connected to the electrodes and also measuresthe three voltages across the three pair of conductors. The hardwareincludes an electrical source and a measurement device 170 having theexcitation entity 178 and measurement entities 182, 184, 186. A fourthmeasurement via the measurement entity 176 is done across a referenceresistor 180 which is in series with this network. The entire network inbetween involving the catheter and the reference resistor is invariantacross various load configurations at the distal end 192 but not knownto start with and needs to be estimated through carefully chosen loadconfigurations. The calibration methods as described herein estimatethis network in order to correctly determine and de-embed themeasurements for any arbitrary load network connected to it at a distallocation.

FIG. 53 is another exemplary embodiment of system 200 with a differentconfiguration for obtaining the measurements. In this embodiment thefourth measurement entity 176 (VM1) is in parallel with the excitationentity 178 to obtain the reference voltage across the excitation entity,while the other three measurements are obtained as mentioned inreference to FIG. 52. The other components in FIG. 53 are substantiallythe same as in the embodiment of FIG. 52. It would be appreciated bythose skilled in the art that there may be other alternateconfigurations for obtaining the measurements and the embodimentsdescribed in reference to FIG. 51, FIG. 52 and FIG. 53 are non-limitingexamples. In general, any four independent measurements would sufficefor estimation of a distal load network.

The measurement entities VM1, VM2, VM3 and VM4 shown as 176, 182, 184and 186 in FIG. 51, FIG. 52 and FIG. 53 respectively are typically, butnot limited to, a set of front end buffers and amplifiers for signalconditioning and noise filtering followed by an analog-to-digitalconverter. The measurement entity may provide frequency dependent gainto the incident signal across it. In an ideal scenario, a voltagemeasurement unit should not draw any current from the network it isconnected to, but in practice it is impossible to implement the same.However, as would be appreciated by those skilled in the art, thevoltage measurement entity can be equivalently modeled as a cascade ofan equivalent parasitic network that accounts for the loading,filtering, and other non-idealities followed by an ideal buffer and gainunit that does not draw any input current and only amplify the incidentvoltage by a fixed amount. Further, the parasitic network can be mergedas a part of the in between catheter network and estimated jointly, asis described in more detail herein below.

FIG. 54 is a terminal representation for the embodiment shown in FIG.52. It will be understood by those skilled in the art that a terminal,generally referred as Tk (Vk, Ik) represents a terminal k whose voltagewith respect to an arbitrary ground, represented as GND 43 is Vk whilethe current entering the network through that terminal is Ik. In thecurrent embodiment, the terminals are defined in the following manner:Terminal-0 (T0), referred also as 44 is the terminal across which avoltage source or a current source 14 is connected. The voltage measuredon Terminal-0 with respect to an arbitrary GND is defined as V0, whilethe current entering the network through T0 is defined as 10.Terminal-1A (T1A) represented by 46 is one of the differential terminalsacross which the first measurement is done. This terminal does notsource or sink any current to the network as these terminals are modeledas ideal measurement points. Terminal-1B represented by 48 pairs withTerminal-1A and behaves similarly to Terminal-1A. Terminal-2A,Terminal-2B are the set of differential terminals for the secondmeasurement. Terminal-3A, Terminal-3B are the terminals for the thirdmeasurements, while Terminal-4A, Terminal-4B are the set of differentialterminals for the fourth measurement. Together, the terminals 2A, 2B,3A, 3B, 4A, 4B are shown by reference numeral 50 and represent theterminals for proximal voltages. Each of these terminals don't source orsink any current. The voltages on these terminals are all measured withreference to the same GND 43.

On the distal side, Terminal-5, Terminal-6, Terminal-7 and Terminal-8,collectively shown as 52, correspond to the four electrodes forming themulti port load network I8 that is connected to the measurement entitiesand excitation source via the multi port interconnecting network I6 asexplained herein above. The voltages on these terminals are referred toas V5, V6, V7 and V8 and are referred to as distal voltages, whereinthese measurements are performed with respect to GND 43. The currentsentering the network through these terminals are referred to as I5, I6,I7 and I8, respectively.

The network can be described completely using Z parameterrepresentations as given below:

V1=Z1*I1  (9)

where, V1 and I1 are given by the following matrices,

V1=[V ₀ V _(1A) V _(1B) V _(2A) V _(2B) V _(3A) V _(3B) V _(4A) V _(4B)V ₅ V ₆ V ₇ V ₈]^(T)

I1=[I ₀ I ₅ I ₆ I ₇ I ₈]^(T)  (10).

Z1 is the impedance matrix of the network relating the current vector I1to the voltage vector V1. In another embodiment, the voltages of node 1,node 2, node 3 and node 4 representing the distal end electrodes, arerepresented differentially as:

V ₁ =V _(1A) −V _(1B)

V ₂ =V _(2A) −V _(2B)

V ₃ =V _(3A) −V _(3B)

V ₄ =V _(4A) −V _(4B)  (11)

Equation (9) can be now re-written as:

V2=Z2*I2  (12)

where, V2 and I2 are given by the following matrices,

V2=[V ₀ V ₁ V ₂ V ₃ V ₄ V ₅ V ₆ V ₇ V ₈]^(T)

I2=[I ₀ I ₅ I ₆ I ₇ I ₈]^(T)  (13)

Z2 is the impedance matrix of the network relating the current vector I2to the voltage vector V2.

FIG. 55 illustrates exemplary system 54 with a floating network on thedistal side. A floating network is defined as one where the sum total ofall currents entering the network through all its ports is equal tozero. No separate electrical path exists between the network and GND. Aport representation on the distal end is shown instead of the terminalrepresentation as is shown in FIG. 54. Port voltages P1, P2, P3, P4 andPL1, PL2, PL3 are defined as differences between two neighboringterminal voltages, the voltage difference being depicted by referencenumerals 56, 58, 60, 62, 64, 66, and 68 respectively, while the portcurrents are defined as the current that enters through one arm of theport and exits the network through another arm of the port.

Those skilled in the art would recognize the equivalence of therepresentation of FIG. 54 and FIG. 55, for a floating network on thedistal side. It would require a few manipulations of rows and columns ofthe system of equations represented by Equation (12) to come to a newset of equations represented by Equation (14).

V=Z*I  (14)

where, V and I are given by,

V=[V ₀ V ₁ V ₂ V ₃ V ₄ V _(L1) V _(L2) V _(L3)]^(T)

I[I ₀ I _(L1) I _(L2) I _(L3)]^(T)  (15)

Z is the impedance matrix of the network relating the current vector Itothe voltage vector V.

The floating network system as described by equation 14 is explained inmore detail herein below. One skilled in the art would be able to extendthe following set of derivations for use cases where the distal networkis not floating. In the network depicted by FIG. 54, V0 is the voltageapplied to the network, I0 is the current getting into the network. Ifthe excitation is a perfect voltage source I4, V0 is fixed to the valueof the voltage source. Similarly, for a perfect current sourceexcitation, I0 is fixed to the value of the current for the currentsource. However in practice, an ideal voltage source or a current sourcedoes not exist. It may be possible to measure the voltage V0 or currentI0 precisely without affecting the network appreciably. However, suchmeasurements would involve intricate electronics especially when thefrequency of excitation is high, and therefore increase the hardwarecomplexity. Aspects of the present technique advantageously overcomethis problem by deriving a method to identify the load network withoutrequiring the knowledge of the voltage V0 or current I0 as explainedherein below.

Since the value of voltage V0 is not needed, it is taken off from thefirst row from the system of equations defined in Equation (14). The newsystem of equations are written as:

V ₁ =Z ₁₀ I ₀ +Z ₁₁ I _(L1) +Z ₁₂ I _(L2) +Z ₁₃ I _(L3) V ₂ =Z ₂₀ I ₀ +Z₂₁ I _(L1) +Z ₂₂ I _(L2) +Z ₂₃ I _(L3)

V ₃ =Z ₃₀ I ₀ +Z ₃₁ I _(L1) +Z ₃₂ I _(L2) +Z ₃₃ I _(L3)

V ₄ =Z ₄₀ I ₀ +Z ₄₁ I _(L1) +Z ₄₂ I _(L2) +Z ₄₃ I _(L3)

V _(L1) =Z ₅₀ I ₀ +Z ₅₁ I _(L1) +Z ₅₂ I _(L2) +Z ₅₃ I _(L3)

V _(L2) =Z ₆₀ I ₀ +Z ₆₁ I _(L1) +Z ₆₂ I _(L2) +Z ₆₃ I _(L3)

V _(L3) =Z ₇₀ I ₀ +Z ₇₁ I _(L1) +Z ₇₂ I _(L2) +Z ₇₃ I _(L3)  (16)

In the exemplary method, the four measured voltages are grouped in avector V_(M) and similarly the load side voltages are grouped in thevector V_(L). The load side currents are similarly grouped in vectorI_(L), as shown in the equations below:

V _(M) =[V ₁ V ₂ V ₃ V ₄]^(T)

V _(L) =[V _(L1) V _(L2) V _(L3)]^(T)

I _(L) =[I _(L1) I _(L2) I _(L3]) ^(T)  (17)

Now re-writing equation (16) using the nomenclature defined above:

V _(M) =Z _(M0) I ₀ +Z _(ML) I _(L)

V _(L) =Z _(L0) I ₀ +Z _(LL) I _(L)  (18)

where, Z_(M0), Z_(ML), Z_(L0) and Z_(LL) are sub-matrices of theimpedance matrix (Z) formed by the grouping of the Z-terms in Eqn (16).

As would be appreciated by those skilled in the art, the distal side(load side) is also terminated by an arbitrary network which can bemodeled as a 3×3 admittance matrix Y related to the load side voltagevector V_(L) and current vector I_(L). For passive networks, theadmittance matrix Y would have 6 independent variables, whereas for ageneral active network the number of variables would be 9. For somespecific scenarios (including that of the one discussed) the loadnetwork may have other constraints and the degrees of freedom is lowerthan 6. In the specific example of FIG. 52, the anatomical constraintswhile measuring the lumen dimensions may drive the degrees of freedom ofthe Y parameters to 3 or less.

Since the current vector I_(L) is shown entering the catheter network, anegative sign is used while representing the following load equation:

I _(L) =YV _(L)  (19)

Using, Equation (19) in Equation (18) the following is derived:

$\begin{matrix}{{V_{L} = {{Z_{L\; 0}I_{0}} + {Z_{LL}I_{L}}}}{V_{L} = {{{Z_{L\; 0}I_{0}} - {Z_{LL}{{YV}_{L}\left( {I + {Z_{LL}Y}} \right)}V_{L}}} = {Z_{L\; 0}I_{0}}}}{V_{L} = {\left( {I + {Z_{LL}Y}} \right)^{- 1}Z_{L\; 0}I_{0}}}\begin{matrix}{V_{M} = {{Z_{M\; 0}I_{0}} - {Z_{ML}{YV}_{L}}}} \\{= {\left( {Z_{M\; 0} - {Z_{ML}{Y\left( {I + {Z_{LL}Y}} \right)}^{- 1}Z_{L\; 0}}} \right)I_{0}}}\end{matrix}{{V_{M}/I_{0}} = {Z_{M\; 0} - {Z_{ML}{Y\left( {I + {Z_{LL}Y}} \right)}^{- 1}Z_{L\; 0}}}}} & (20)\end{matrix}$

Since I₀ is assumed to be unknown, to resolve a situation where theresults would have a scale factor ambiguity, a ratio of two voltages isused instead of the absolute voltage. Without a loss of generality, thevoltage across the reference resistor of FIG. 52 is used, as thereference voltage, V₁ and all other voltages are measured as a ratio tothe reference voltage.

$\begin{matrix}\begin{matrix}{{\frac{V_{M}}{V_{1}} = \frac{\left( {Z_{M\; 0} - {Z_{ML}{Y\left\lbrack {I + {Z_{LL}Y}} \right\rbrack}^{- 1}Z_{L\; 0}}} \right)}{\left( {Z_{10} - {Z_{IL}{Y\left\lbrack {I + {Z_{LL}Y}} \right\rbrack}^{- 1}Z_{L\; 0}}} \right)}};} & {{{{{where}\mspace{14mu} M} = 2},3,4}} \\{{= \frac{\left\lbrack {\left( \frac{Z_{M\; 0}}{Z_{10}} \right) - {Z_{ML}{L\left\lbrack {I + {Z_{LL}Y}} \right\rbrack}^{- 1}\left( \frac{Z_{L\; 0}}{Z\; 10} \right)}} \right\rbrack}{1 - {Z_{1L}{Y\left\lbrack {I + {Z_{LL}Y}} \right\rbrack}^{- 1}\left( \frac{Z_{L\; 0}}{Z_{10}} \right)}}};} & {{{{{where}\mspace{14mu} M} = 2},3,4}} \\{= \frac{\overset{\_}{Z_{M\; 0}} - {Z_{ML}{Y\left\lbrack {1 + {Z_{LL}Y}} \right\rbrack}^{1}\overset{\_}{Z_{L\; 0}}}}{1 - {Z_{1\; L}{Y\left\lbrack {1 + {Z_{LL}Y}} \right\rbrack}^{1}\overset{\_}{Z_{L\; 0}}}}} & {{{{{where}\mspace{14mu} M} = 2},3,4}}\end{matrix} & (21)\end{matrix}$

where, Z_(M0) and Z_(L0) are normalized by Z_(I0), and Z_(I0) is fixedto unity.

(Thus these equations effectively model the effect of an arbitrary loadnetwork connected at a distal end to the measurements done at a proximalend.

In the formulation above, voltage ratios VM/V1 are used. This is becausethe exact value of V0 (in the case of voltage excitation) or I0 (in thecase of current excitation) is not known precisely in normal practicalsituations. However, if these can be determined with enough precision,the calibration method can be formulated with absolute voltages ratherthan voltage ratios. As such, the disclosure envisages such alternateformulations where the voltages can be used in forms other than ratiossuch as absolute value, voltage differences, linear or non-linearcombinations of the voltages.

The exemplary method as described herein uses the above system model fordetermining the actual voltage difference measurements for an arbitraryload network connected at the distal end through proximal measurements.The next step for the method is to identify the Z parameters of theconnecting network along with measurement parasitics, herein referred toas the calibration step. Thereafter, a step of de-embedding is donewherein, the proximal measurements are mapped to (or, fitted to) thedistal load network after due consideration for the Z parameters of theconnecting network and measurement parasitics.

In the process of calibration described herein, the three voltage ratioswith respect to the first voltage is measured for different combinationsof precisely known load networks connected on the distal end. It may benoted that for a passive load network, in Equation (21), the number ofunknown Z-parameters to be estimated is 23. The Z parameters areobtained using a suitable fitting utility that runs on the set ofmeasured data. Since every configuration provides three voltages, it isnecessary to have at least measurements from 8 independentconfigurations to obtain all the Z parameters. More configurationsprovide better noise immunity to the fitted values. The fitter routinestarts with an arbitrary starting point and computes the estimatedratios of voltages across different known load configurations forEquation (21). The method then computes an error metric which is theEuclidian distance between the measured ratios and the estimated ratios.The fitter tries to minimize this error by adjusting the Z parametervalues. It is possible for the solution to converge to alternatesolutions. However, skilled persons in this art would recognize thesechallenges and come up with suitable techniques to circumvent them. Thiscan be done by employing suitable optimization techniques. It may benoted that the fitted Z parameters are not the true Z parameters of thenetwork but are a mathematical representation that fits the observationunder the constraints of one pre-determined Z-parameter (any one ofZL0). Further, a few Z-parameters are normalized to ZI0 and ZI0 is fixedto unity, as was mentioned earlier.

Once the Z parameters have been estimated through the process ofcalibration, the connecting network can be used to identify anyarbitrary load network at the distal end. In specific applications, suchas but not limited to the embodiment of FIG. 52 where a catheter withfour distal electrodes (connecting network) is inserted inside a lumenand the load presented on the distal side is due to the finiteconductivity of blood inside the lumen or the finite conductivity ofwall tissue, the degrees of freedom for the network is 3. The threevoltage distributions across the three electrodes completely define theZ-parameters of the equivalent electrical network formed by theelectrodes inside the lumen. Similar applications such as measurement ofa cross section of a pipe electrically through similar means would alsohave similar degrees of freedom. Once a measurement of three ratios aretaken for an arbitrary load network (with Admittance Y with 3 degrees offreedom), a similar fitter routine can be used to find out the loadnetwork. In one example, the fitter routine is initialized by a startingvalue of Y, which is the best case estimate given by the user. Theratios are accordingly estimated (according to Equation 21) and an errormetric is computed as the difference between the measured ratios and theestimated ratios. The error metric is then minimized by adjusting the Yparameters of the load network. The Y parameters representing the lowesterror represent the true Y parameter of the load network.

It may be noted that since only three ratios are measured, this methodis applicable to identification of networks which has no more than 3degrees of freedom. As discussed, for an arbitrary network with threeports, the Y parameter can have 9 degrees of freedom. For passivenetworks, the degrees of freedom are typically 6. Identification of suchnetworks can also be done using extension of the exemplary method. Toidentify a passive arbitrary load network (with 6 degrees of freedom),the calibration and de-embedding processes needs to be done for twoindependent interconnecting networks. In practice, it can also beachieved by taking two measurements, one with the actual interconnectingnetwork and the other with a modified version of the same. During thecalibration phase, precisely known loads are attached to the distal sideof the connecting network and the three ratios are measured and whilemaintaining the same load, the connecting network is modified using areversible mechanism (such as a relay 72 shorting the two center ports 2and 3 at the proximal end of the embodiment 70 of FIG. 56) and the newratios are measured.

The same procedure is then repeated for various load configurations.Using similar principles of the calibration phase, the Z parameters areestimated both for the parent connecting network as well as its modifiedversion. Finally, an arbitrary passive load network is connected distalto the same connecting network. The three ratios are measured once withthe original connecting network and a second time when the connectingnetwork has been modified as before. A total of six ratios are obtainedand with the knowledge of the Z parameters of the connecting network andits modified version from the calibration phase, it would be possible tounravel all the 6 degrees of freedom of the load network. The method canbe also be extended to unravel an arbitrary active three port networkwith 9 degrees of freedom, by performing measurements using threedifferent connecting networks.

In an alternate embodiment, an n-port load network is represented by Lindependent (L=n2) complex impedances. As would be appreciated byskilled persons in this art, the complex impedances bear equivalencewith the Z-parameters of the same network. For a passive load network,the number of independent complex impedances would be P (=n*(n−1)),since the network would be symmetric. FIG. 57 represents an embodiment74 with an exemplary 3-port passive network 76 with 6 complex impedancesshown generally by reference numeral 78. Any other passive 3-portnetwork topology can be reduced to an equivalent network 76 with thetopology shown in the embodiment 80 of FIG. 58 as well. Other componentsrelated to the excitation and measurement entity remain substantiallythe same as described in earlier figures.

According to network theory, as would be well understood by thoseskilled in the art, for any network consisting of an ordered set ofdiscrete impedances, the voltage across any two points (u, v) in thenetwork can be represented as a product of the excitation voltage or,excitation current (ξ0) and a ratio of sum of polynomials formed by allthe impedances present in the network. The denominator polynomial isreferred to as the characteristic polynomial of the network consistingof all the impedances in the network. The characteristic polynomial isindependent of the points of measurements. Further, if some part of thenetwork consists of distributed elements and other parts consist ofdiscrete impedances, the voltage can still be represented as a productof ξ0 and the ratio of sum of polynomials formed by all the discreteimpedances present in the network, wherein the coefficients of thepolynomial would capture the effects of the distributed elements.

If some of the discrete impedances are of interest, the polynomials canbe regrouped into a polynomial of just the discrete impedances ofinterest. In this case, the coefficients of the re-grouped polynomialwould contain the effects of the other discrete impedances as well asthe distributed elements of the network.

Referring to FIG. 50, where the measurement network 170 and theconnecting network 172 are fixed while the multi-port load network 174is allowed to change through variations of L number of load impedances(Z₁, Z₂, . . . Z_(L)), the voltage between any two points (u, v) in thenetwork can be written as:

$\begin{matrix}{{V\left( {u,v} \right)} = {\xi_{0}\frac{\begin{matrix}{{b_{0}\left( {u,v} \right)} + {\sum\limits_{i}{{b_{1i}\left( {u,v} \right)}Z_{i}}} +} \\{{\sum\limits_{i}{\sum\limits_{j,{i \neq j}}{{b_{2{ij}}\left( {u,v} \right)}Z_{i}Z_{j}}}} + \ldots + {{b_{L}\left( {u,v} \right)}Z_{i}Z_{j}\mspace{14mu} \ldots \mspace{14mu} Z_{L}}}\end{matrix}}{{1 + {\sum\limits_{i}{a_{1\; i}Z_{i}}} + {\sum\limits_{i}{\sum\limits_{i,{i \neq j}}{a_{2{ij}}Z_{i}Z_{j}}}} + \ldots + {a_{L}Z_{i}Z_{j}\mspace{14mu} \ldots \mspace{11mu} Z_{L}}}\;}}} & (22)\end{matrix}$

In general, each of the L number of load impedances contributes to thevoltage distribution within the network. The contribution of fixedelements within the network is absorbed in the polynomial coefficients.The denominator is equivalent to the characteristic polynomial for thecombined network (170, 172 and 174), and its coefficients (a's) arefixed for the given network and depends on network 172 and 174.

In specific instances, where only the port's self-impedances are ofsignificance, the entire n-port load network can be represented by ncomplex impedances. In this scenario, the Z-parameter for the networkwould be a diagonal matrix with n diagonal terms. FIG. 57 describes anexemplary embodiment where the number of ports (n) is 3. For such anetwork, with three impedances (Z₁, Z₂ and Z₃) on the distal side, thevoltage measurements in the proximal side (e.g. V₁, V₂, V₃, V₄) is givenby:

$\begin{matrix}{{{V_{i} = {\xi_{0}\frac{\begin{matrix}{{b_{0}(i)} + {{B_{11}(i)}Z_{1}} + {{b_{12}(i)}Z_{2}} + {{b_{12}(i)}Z_{3}} +} \\{{{b_{212}(i)}Z_{1}Z_{2}} + {{b_{223}(i)}Z_{2\;}Z_{3}} + {{b_{231}(i)}Z_{3}Z_{1}} + {{b_{3}(i)}Z_{1\;}Z_{2}Z_{3}}}\end{matrix}}{\begin{matrix}{1 + {a_{11}Z_{1}} + {a_{12}Z_{2}} + {a_{13}Z_{3}} + {a_{212}Z_{1}Z_{2}} +} \\{{a_{223}Z_{2}Z_{3}} + {a_{221}Z_{3}Z_{1}} + {a_{3}Z_{1}Z_{2}Z_{3}}}\end{matrix}}}};}\mspace{20mu} {{i = 1},2,3,4}} & (23)\end{matrix}$

Instead of the absolute measurements in the proximal end, one can alsowork on voltage ratios to avoid dependencies on the excitation voltageor, excitation current (ξ₀). Without loss of generality, the voltageacross the reference resistor (V₁) is taken as reference and threeratios are constructed with respect to V₁.

$\begin{matrix}{{\frac{V_{i}}{V_{l}} = {{\frac{\begin{matrix}{{b_{0}(i)} + {{b_{11}(i)}Z_{1}} + {{b_{12}(i)}Z_{3}} + {{b_{13}(i)}Z_{3}} + {{b_{212}(i)}Z_{1\;}Z_{2}} +} \\{{{b_{222}(i)}Z_{2}Z_{3}} + {{b_{221}(i)}Z_{3}Z_{1}} + {{b_{3}(i)}Z_{1}Z_{2}Z_{3}}}\end{matrix}}{\begin{matrix}{{b_{0}(l)} + {{b_{11}(l)}Z_{1}} + {{b_{12}(l)}Z_{3}} + {{b_{13}(l)}Z_{3}} + {{b_{212}(l)}Z_{1\;}Z_{2}} +} \\{{{b_{222}(l)}Z_{2}Z_{3}} + {{b_{221}(l)}Z_{3}Z_{1}} + {{b_{3}(l)}Z_{1}Z_{2}Z_{3}}}\end{matrix}}.i} = 2}},3,4} & (24)\end{matrix}$

The properties of the measurement and the connecting networks arerepresented by the polynomial coefficients. For a network with nimpedances and (n+1) measurement entities, the number of independentpolynomial coefficients would be (n+1)*2n−1. It may be noted that allthe polynomial coefficients in Equation (24) can be scaled by the firstterm in the denominator, thereby reducing one unknown. The act ofcalibrating these networks would involve making proximal measurementswith known impedances connected to the distal ports. The number of suchindependent measurements required would depend on the number of unknownsthat need to be solved and the number of information per measurement. Afitter routine would then run on all of these measurement ratios, forknown set of loads and estimate the polynomial coefficients.

Once the process of calibration is completed, and the polynomialcoefficients are obtained, any arbitrary load connected across thedistal ports in a similar configuration can be estimated. With anarbitrary load connected across the distal ports in a similarconfiguration, the proximal measurements are made and the ratios arecomputed with respect to the reference measurement. Next a fitterroutine is invoked with the pre-determined polynomial coefficients andthe ratios corresponding to the arbitrary load. The fitter routine maybe initialized by the user with a starting value of the load impedancesbased on best guess. The fitter shall converge to a minimal residue onfinding the true value for impedances which would match the ratio ofmeasurements. Convergence to alternate solutions are possible, howeverskilled persons in this art would be adept in avoiding such situations.

To estimate a generalized three port passive load network which can bemodeled by six independent impedances, one would need to write thepolynomial equations in Equation (22) with all six impedance present.Since the numbers of ratios measured are only three, the method needs tobe extended for measurement of six impedances as discussed before. Themethod of calibration would involve making measurements with variouscombinations of load networks (comprised of all six impedances) for twoindependent interconnecting networks. The polynomial coefficients forboth these networks would then be estimated using the individual sets ofmeasurement ratios and the knowledge of load impedances. Next,measurements would be made with arbitrary six impedance load networks,again with the same two independent interconnecting networks. A total ofsix ratios along with the polynomial coefficients for both the networkswould jointly be fitted by a fitter routine for estimating the siximpedances. The method can similarly be extended to active networkswhere a nine impedance model needs to be estimated.

The above method, exemplified by a three port network with four proximalmeasurement entities can be easily extended to a general n-port networkwith n+1 proximal measurement entities on basis of Equation (22). Thecomputation complexity grows exponentially with increasing number ofload impedances in the network.

Thus the methods described herein can be extended to de-embed andevaluate a generalized n-port load network where there are n+1measurements performed concurrently.

Any electrical measurement is corrupted due to noise and otherinaccuracies of the measurement system. Due to inaccuracies ofmeasurements, the process of calibration and de-embedding would resultin inaccurate estimates of system parameters such as lumen dimension.For a given choice of measurement nodes, the measurement inaccuraciesmay show a flared up or, subdued effect on the estimated valuesdepending on the transformation caused by the intervening network. Hencethe choice of measurement nodes needs to be made such that the accuracyof estimated parameters is maximized for the given intervening network.This can be done analytically, through simulations or, through physicalexperimentations.

The methods as described herein above are also depicted in the form offlowchart 82 of FIG. 59. The calibration technique for use inmeasurements from a remotely located multi port network, is shown bysteps 84 to 92 of the flowchart, and includes a step 84 of providing anexcitation and measurement entity for exciting the remotely locatedmulti port network and for measuring a plurality of proximal voltagescorresponding to the remotely located multi port network; a step 86 ofproviding a connecting network for connecting the excitation andmeasurement entity and the remotely located multi port network; a step88 providing a plurality of known load networks coupled to theconnecting network. The calibration technique further includes a step 90for measuring a set of voltage ratios corresponding to each load of theknown load networks; and a step 92 for estimating electrical parameterscorresponding to the measurement entity and the connecting network byusing a fining utility across the set of voltage ratios, where theelectrical parameters are used for calibration. The method furtherincludes a step 94 for using the electrical parameters to de-embed themeasurements from the remotely located multi port network.

The embodiments described herein have been illustrated through use of Zparameters as electrical parameters for modeling the electrical network.As would be appreciated by those skilled in the art, using the sameprinciples, a similar formulation can also be made using Y parameters, Sparameters, H parameters and G parameters since all models areequivalent ways of representing the electrical network. As such, it isto be understood that the embodiments described herein covers all suchformulations.

The technique described herein can be effectively used for determiningactual voltages or voltage differences between the measuring electrodesor terminals of a remotely located multi-port network.

The method as described herein above maybe incorporated as a tool thatis used to determine the voltages or any other electrical response froma remotely located multi-port network.

In a specific example, a system for de-embedding measured proximalvoltages across conductors connected to at least three electrodes placedin vivo in a body lumen is also disclosed. The system may include theembodiments of FIGS. 50-53 having an excitation and measurement entityfor exciting the at least three electrodes and for measuring a pluralityof proximal voltages corresponding to the at least three electrodes. Thesystem also includes a connecting network in the form of two or moreconductors for connecting the excitation and measurement entity and theat least three electrodes, where the at least three electrodes are at adistal end of the two or more conductors. A processor is added in theembodiments of FIGS. 50-53 coupled to the excitation and measuremententities and the connecting network for estimating a plurality ofelectrical parameters as calibration parameters corresponding to theexcitation and measurement entity and the connecting network, and forestimating actual voltages across the at least two pair of the at leastthree electrodes using the electrical parameters to de-embed themeasured proximal voltages.

It would be appreciated by those skilled in the art that the embodimentsdescribed herein for example the embodiments of FIGS. 50-53, pertain tocompensating for the effects to both, the excitation and measuremententity 14 and the multi-port interconnection network 16. However, insome practical situations, it may be necessary to calibrate the effectsof each of the entities separately, and during the process ofde-embedding, the effects of both the entities will be combined.Further, the multi-port interconnection network 16 may include multipleparts or components. In this case, and each part would be calibratedseparately and the parameters can be combined together at the time ofde-embedding. It is to be understood that this divided approach forcalibration and de-embedding is also within the scope of the inventionas described herein.

As used herein, the singular forms “a,” “an,” and “the” include theplural reference unless the context clearly indicates otherwise.

As used herein, lumen includes the volume defined by any generallyelongate, sometimes tubular, structured component of a subject such as ahuman being, such as an artery or intestine. For example, the interiorof a vessel, such as the inner space in an artery or vein through whichblood flows is considered a lumen. Lumen also includes a particularportion of the generally tubular structured component of a subject, suchas a section of aorta near the heart, for example. The particularsection of the lumen may be of interest to a doctor, for example, as itmay comprise some features associated with it, such as a blockage or astenosis. Thus, in some instances, lumen as used herein, may also bereferred herein as volume of interest, a region of interest, or a lumenof interest.

An electrical network as referred herein is an interconnection ofelectrical elements such as resistors, inductors, capacitors,generalized frequency dependent impedances, conductor wires, voltagesources, current sources and switches.

A terminal is the point at which a conductor from an electricalcomponent, device or network comes to an end and provides a point ofconnection to external circuits. A terminal may simply be the end of awire or it may be fitted with a connector or fastener. In networkanalysis, terminal means a point at which connections can be made to anetwork in theory and does not necessarily refer to any real physicalobject.

An electrical connector is an electro-mechanical device for joiningelectrical circuits as an interface using a mechanical assembly. Theconnection may be temporary, as for portable equipment, or may require atool for assembly and removal, or may be a permanent electrical jointbetween two wires or devices.

As used herein electrical measurements include measurable independent,semi-independent, and dependent electrical quantities including forexample voltage by the means of voltmeter (or using oscilloscope,including pulse forms), electric current by the means of ammeter,electrical resistance, conductance, susceptance and electricalconductance by the means of ohmmeter, magnetic flux and magnetic fieldby means of a Halls sensor, electrical charge by the means ofelectrometer, electrical power by the means of electricity meter,electrical power spectrum by the means of spectrum analyzer.

Electrical impedance as referred herein is defined as vector sum ofelectrical resistance and electrical reactance. Inductance is defined asfrequency proportionality coefficient for reactance, and capacitancedefined as reciprocal frequency proportional coefficient for reactance.

Electrical impedance as referred to herein is defined as a vector sum ofelectrical resistance and electrical reactance. Inductance is defined asfrequency proportionality coefficient for reactance, and capacitancedefined as reciprocal frequency proportional coefficient for reactance.

Voltage between any two points as generally referred herein is theelectrical potential difference between the two points and is alsoreferred herein as voltage difference or voltage drop.

The process of estimating the effects of electrical properties of anintervening multiport network is referred to as calibration. The processof using the estimated properties of the network to compensate for thenetwork and obtain the compensated measurement is referred tode-embedding.

Z-parameters (the elements of an impedance matrix or Z-matrix) referredto herein are the impedance parameters for an electrical network. TheZ-parameters are also known as the open circuit parameters. Fordetermining the kth column of the Z matrix, all but the kth port areopened, current is injected on the kth port, and the voltages areanalyzed on all ports. The procedure is performed for all N ports (k=1to N) to obtain the entire Z matrix. Though the exemplary embodimentshave been described using Z parameters, the methods and systemsdescribed herein are equally applicable to other parameters such as Y,S, H, and G parameters.

A generic multi-port network referred to herein includes ports 1 to N,where N is an integer depicting the total number of ports. For port n,where n is ranging from 1 to N, the associated input current throughthat port to the network is defined as In and the voltage across thatport is defined as Vn.

As used herein, the phrase “peak-to-rms-ratio” (“PAR”) means the valueobtained for a waveform by the division of peak amplitude of thewaveform by the root mean square value for the waveform. It is adimensionless number generally expressed as a ratio of a positiverational number to one. It is also known in the art as “crest factor,”peak-to-average ratio, or by other similar terms, known to those ofordinary skill in the art. PAR values for a variety of standardwaveforms are generally known. PAR values may be obtained fromtheoretical calculations, or they may be measured using some PAR metersfor specific situations.

As used herein, the phrase “Signal to noise ratio” (often abbreviated“SNR” or “S/N”) means the ratio of signal power to the noise powerassociated with the signal. The noise power is considered to corrupt thesignal power. Hence, SNR is a measure to quantify how much a signal hasbeen corrupted by noise. Ideally, a good SNR should have a ratio muchhigher than 1:1.

While preferable embodiments have been shown and described herein, itwill be obvious to those skilled in the art that such embodiments areprovided by way of example only. Numerous variations, changes, andsubstitutions will now occur to those skilled in the art withoutdeparting from aspects of the disclosure. It should be understood thatvarious alternatives to the embodiments of the disclosure describedherein may be employed in practicing the disclosure.

1. A method of determining information about a vascular bodily lumen,comprising: generating a multiple-frequency electrical signal at aplurality of frequencies; delivering the multiple frequency electricalsignal to a plurality of excitation elements in the vicinity of thevascular bodily lumen; measuring an electrical signal from a pluralityof sensing elements at least two of the plurality of frequencies inresponse to the delivered signal; determining a lumen dimension usingthe measured electrical signal at the at least two frequencies, whereindetermining the lumen dimension comprises comparing the measuredelectrical signal with a modeled electrical signal to determine lumendimensions.
 2. The method of claim 1 wherein the measuring stepcomprises measuring voltages across the plurality of sensing elements atthe at least two of the plurality of frequencies.
 3. The method of claim2 wherein determining the lumen dimension comprises converting thevoltages to one or more lumen dimensions.
 4. The method of claim 1wherein the method does not include injecting a fluid into the vascularbodily lumen.
 5. The method of claim 1 wherein determining the lumendimension comprises comparing a measured voltage with a modeled voltage.6. The method of claim 5 wherein the modeled voltage is based on amodeled lumen dimension.
 7. The method of claim 6 wherein the modeledlumen dimension is a lumen cross sectional area.
 8. The method of claim1 wherein the comparing step comprises comparing the measured electricalsignal with an electrical signal from a look-up table.
 9. The method ofclaim 8 wherein the electrical signal from the look-up table is avoltage.
 10. The method of claim 1 wherein generating a multiplefrequency sequence pulse comprises generating a multiple-frequencysequence pulse having a predetermined peak to root-to-mean-square (rms)ratio.
 11. A method of determining information about a vascular bodilylumen, comprising: generating an electrical signal; delivering theelectrical signal to a plurality of excitation elements in the vicinityof the vascular bodily lumen; measuring a responsive electrical signalfrom a plurality of sensing elements in response to the deliveredelectrical signal; and, determining a lumen dimension, whereindetermining the lumen dimension does not include measuring a secondresponsive electrical signal and does not include information obtainedfrom any previous measurements.
 12. The method of claim 11 whereinmeasuring the responsive electrical signal comprises measuring aplurality of responsive signals at a plurality of frequencies.
 13. Themethod of claim 12 wherein the measuring step comprises measuringvoltages across the plurality of sensing elements at least two of theplurality of frequencies.
 14. The method of claim 13 wherein determiningthe lumen dimension comprises converting the voltages to one or morelumen dimensions.
 15. The method of claim 12 wherein measuring theresponsive signals at the plurality of frequencies occurssimultaneously.
 16. The method of claim 11 wherein determining the lumendimension comprises iteratively comparing the measured electrical signalwith a modeled electrical signal to determine the lumen dimension. 17.The method of claim 16 wherein the comparing step comprises comparing ameasured voltage with a modeled voltage.
 18. The method of claim 16wherein the modeled voltage is based on a modeled lumen dimension. 19.The method of claim 18 wherein the modeled lumen dimension is a lumencross sectional area.
 20. The method of claim 11 wherein the comparingstep comprises comparing the measured electrical signal with anelectrical signal from a look-up table.
 21. The method of claim 20wherein the electrical signal from the look-up table is a voltage.
 22. Amethod of determining information about a bodily lumen, comprising:generating an electrical signal; delivering the electrical signal to aplurality of excitation elements in the vicinity of the bodily lumen;measuring a responsive electrical signal from a plurality of sensingelements in response to the delivered electrical signal, whereinmeasuring the responsive signal does not include replacing a volume ablood with fluid; determining a lumen dimension, wherein determining thelumen dimension does not include measuring a second responsiveelectrical signal.
 23. The method of claim 22 wherein determining thelumen dimension comprises comparing the measured electrical signal witha modeled electrical signal to determine the lumen dimension.
 24. Themethod of claim 23 wherein the comparing step comprises comparing ameasured voltage with a modeled voltage.
 25. A medical device adapted todetermine information about a vascular bodily lumen, comprising: anelongate device; a plurality of excitation elements and a plurality ofsensing elements disposed on the elongate device; and, a controller incommunication with the plurality of excitation elements, where thecontroller is configured to generate a multiple-frequency electricalsignal at a plurality of frequencies from the plurality of excitationelements, wherein a first of the plurality of sensing elements is notequally spaced from second and third sensing elements.
 26. The medicaldevice of claim 25 wherein the first sensing element is disposed axiallybetween the second and third sensing elements on the elongate device.27. The medical device of claim 25 wherein the second and third sensingelements are also first and second excitation elements.
 28. The medicaldevice of claim 25 wherein the elongate device is a guidewire, andwherein the excitation elements and sensing elements are electrodes. 29.The medical device of claim 25 wherein the elongate device is anangioplasty balloon catheter and wherein the excitation elements and thesensing elements are electrodes.
 30. The medical device of claim 25wherein the elongate device is a stent delivery catheter, and whereinthe excitation elements and the sensing elements are electrodes.